Thio-substituted arylmethanesulfinyl derivatives

ABSTRACT

The present invention is related to chemical compositions, processes for the preparation thereof and uses of the composition. Particularly, the present invention relates to compositions of compounds of Formula (A): 
                         
wherein Ar, X, Y, R 1 , R 2 , R 3 , and q are as defined herein; and their use in the treatment of diseases, including treatment of sleepiness, promotion of wakefulness, treatment of Parkinson&#39;s disease, cerebral ischemia, stroke, sleep apneas, eating disorders, stimulation of appetite and weight gain, treatment of attention deficit hyperactivity disorder (“ADHD”), enhancing function in disorders associated with hypofunctionality of the cerebral cortex, including, but not limited to, depression, schizophrenia, fatigue, in particular, fatigue associated with neurologic disease, such as multiple sclerosis, chronic fatigue syndrome, and improvement of cognitive dysfunction.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority of U.S. patent application Ser. No. 11/104,074, filed Apr. 12, 2005, which claims priority to U.S. Provisional Application Ser. No. 60/568,991, filed May 7, 2004 and European Patent Application No. 04290983.8, filed Apr. 13, 2004. The disclosures of these prior applications are incorporated herein by reference in their entireties for all purposes.

FIELD OF THE INVENTION

The present invention is related to chemical compositions, processes for the preparation thereof and uses of the composition. Particularly, the present invention relates to compositions of compounds of Formula (A):

and their use in the treatment of diseases, including treatment of sleepiness, promotion and/or improvement of wakefulness, preferably improvement of wakefulness in patients with excessive sleepiness associated with narcolepsy, sleep apnea, preferably obstructive sleep apnea/hypopnea, and shift work disorder; treatment of Parkinson's disease; Alzheimer's disease; cerebral ischemia; stroke; eating disorders; attention deficit disorder (“ADD”), attention deficit hyperactivity disorder (“ADHD”); depression; schizophrenia; fatigue, preferably fatigue associated with cancer or neurological diseases, such as multiple sclerosis and chronic fatigue syndrome; stimulation of appetite and weight gain and improvement of cognitive dysfunction.

BACKGROUND OF THE INVENTION

The compounds disclosed herein are related to the biological and chemical analogs of modafinil. Modafinil, C₁₅H₁₅NO₂S, also known as 2-(benzhydrylsulfinyl)acetamide, or 2-[(diphenylmethyl) sulfinyl]acetamide, a synthetic acetamide derivative with wake-promoting activity, has been described in French Patent No. 78 05 510 and in U.S. Pat. No. 4,177,290 (“the '290 patent”). It has been approved by the United States Food and Drug Administration for use in the treatment of excessive daytime sleepiness associated with narcolepsy. Methods for preparing modafinil and several derivatives are described in the '290 patent. The levorotatory isomer of modafinil, along with additional modafinil derivatives are described in U.S. Pat. No. 4,927,855, and are reported to be useful for treatment of hypersomnia, depression, Alzheimer's disease and to have activity towards the symptoms of dementia and loss of memory, especially in the elderly.

Modafinil has also been described as a useful agent in the treatment of Parkinson's disease (U.S. Pat. No. 5,180,745); in the protection of cerebral tissue from ischemia (U.S. Pat. No. 5,391,576); in the treatment of urinary and fecal incontinence (U.S. Pat. No. 5,401,776); and in the treatment of sleep apneas and disorders of central origin (U.S. Pat. No. 5,612,379). In addition, modafinil may be used in the treatment of eating disorders, or to promote weight gain or stimulate appetite in humans or animals (U.S. Pat. No. 6,455,588), or in the treatment of attention deficit hyperactivity disorder (U.S. Pat. No. 6,346,548), or fatigue, especially fatigue associated with multiple sclerosis (U.S. Pat. No. 6,488,164). U.S. Pat. No. 4,066,686 describes various benzhydrylsulphinyl derivatives as being useful in therapy for treating disturbances of the central nervous system.

Several published patent applications describe derivative forms of modafinil and the use of modafinil derivatives in the treatment of various disorders. For example, PCT publication WO 99/25329 describes various substituted phenyl analogs of modafinil as being useful for treating drug-induced sleepiness, especially sleepiness associated with administration of morphine to cancer patients. U.S. Pat. No. 5,719,168 and PCT Publication No. 95/01171 describe modafinil derivatives that are useful for modifying feeding behavior. PCT Publication No. 02/10125 describes several modafinil derivatives of modafinil, along with various polymorphic forms of modafinil.

Additional publications describing modafinil derivatives include U.S. Pat. No. 6,492,396, and PCT Publication No. WO 02/10125.

Terauchi, H, et al. described nicotinamide derivatives useful as ATP-ase inhibitors (Terauchi, H, et al, J. Med. Chem., 1997, 40, 313-321). In particular, several N-alkyl substituted 2-(Benzhydrylsulfinyl)nicotinamides are described.

U.S. Pat. Nos. 4,980,372 and 4,935,240 describe berizoylaminophenoxybutanoic acid derivatives. In particular, sulfide derivatives of modafinil containing a phenyl and substituted phenyl linker between the sulfide and carbonyl, and a substituted aryl in the terminal amide position, are disclosed.

Other modafinil derivatives have been disclosed wherein the terminal phenyl groups are constrained by a linking group. For example, in U.S. Pat. No. 5,563,169, certain xanthenyl and thiaxanthenyl derivatives having a substituted aryl in the terminal amide position are reported.

Other xanthenyl and thiaxanthenyl derivatives are disclosed in Annis, I; Barany, G. Pept. Proc. Am. Pept. Symp. 15^(th) (Meeting Date 1997) 343-344, 1999 (preparation of a xanthenyl derivative of Ellman's Reagent, useful as a reagent in peptide synthesis); Han, Y.; Barany, G. J. Org. Chem., 1997, 62, 3841-3848 (preparation of S-xanthenyl protected cysteine derivatives, useful as a reagent in peptide synthesis); and El-Sakka, I. A., et al. Arch. Pharm. (Weinheim), 1994, 327, 133-135 (thiaxanthenol derivatives of thioglycolic acid).

Thus, there is a need for novel classes of compounds that possess the beneficial properties. It has been discovered that a class of compounds, referred to herein as substituted thioacetamides, are useful as agents for treating or preventing various diseases or disorders disclosed herein.

SUMMARY OF THE INVENTION

The present invention in one aspect is directed to various novel compounds of formula (A):

and its stereoisomeric forms, mixtures of stereoisomeric forms, or pharmaceutically acceptable salt forms thereof, wherein the constituent members are defined infra.

Another object of the present invention is to provide pharmaceutical compositions comprising the compounds of the present invention wherein the compositions comprise one or more pharmaceutically acceptable excipients and a therapeutically effective amount of at least one of the compounds of the present invention, or a pharmaceutically acceptable salt or ester form thereof.

Another object of the present invention is to provide methods of treating or preventing diseases or disorders, including treatment of sleepiness, promotion and/or improvement of wakefulness, preferably improvement of wakefulness in patients with excessive sleepiness associated with narcolepsy, sleep apnea, preferably obstructive sleep apnea/hypopnea, and shift work disorder; treatment of Parkinson's disease; Alzheimer's disease; cerebral ischemia; stroke; eating disorders; attention deficit disorder (“ADD”), attention deficit hyperactivity disorder (“ADHD”); depression; schizophrenia; fatigue, preferably fatigue associated with cancer or neurological diseases, such as multiple sclerosis and chronic fatigue syndrome; stimulation of appetite and weight gain and improvement of cognitive dysfunction.

These and other objects, features and advantages of compounds of formula (A) will be disclosed in the following detailed description of the patent disclosure.

DETAILED DESCRIPTION OF THE INVENTION

In a first embodiment, the present invention provides novel compounds of formula (A):

wherein:

-   Ar is independently selected from C₆-C₁₀ aryl and 5 to 10-membered     heteroaryl wherein:     -   C₆-C₁₀ aryl and heteroaryl are optionally substituted with one         to three groups selected from F, Cl, Br, I, OR²², OR²⁵, NR²³R²⁴,         NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,         C₃-C₇ cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5 or 6         membered heteroaryl, arylalkyl, C(═O)R²², CO₂R²², OC(═O)R²²,         C(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²¹C R²², OC(═O)NR²³R²⁴,         NR²¹C(═S)R²², and S(O)_(y)R²²; -   X is O, S(O)_(y), N(R¹⁰), OC(R²²)₂, C(R²²)₂O, C(R²²)₂NR²²,     NR²¹C(R²²)₂, C(═O)N(R²¹), NR²¹C(═O), S(O)₂NR²², NR²²S(O)₂,     C(R²²)₂C(R²²)₂, CR²¹═CR²¹, C≡C; -   Y is C₁-C₆ alkylene; or     -   (C₁-C₄ alkylene)_(m)-Z—(C₁-C₄ alkylene)_(n);     -   wherein said alkylene groups are optionally substituted with one         to three R²⁰ groups; -   Z is O, NR^(10A), S(O)_(y), CR²¹═CR²¹, C≡C, C₆-C₁₀arylene, 5-10     membered heteroarylene, C₃-C₆ cycloalkylene, or 3-6 membered     heterocycloalkylene; wherein said arylene, heteroarylene,     cycloalkylene, and heterocycloalkylene groups are optionally     substituted with one to three R²⁰ groups; -   R¹ is selected from H, C₆-C₁₀ aryl, NR¹²R¹³, NR²¹C(═O)R¹⁴, C(═O)R¹⁴,     CO₂R¹¹, OC(═O)R¹¹, C(═O)NR¹²R¹³, C(═NR¹¹)NR¹²R¹³, OC(═O)NR¹²R¹³,     NR²¹S(O)₂R¹¹, NR²¹C(═O)NR¹²R¹³, and NR²¹S(O)₂NR¹²R¹³;     -   wherein said aryl groups are optionally substituted with one to         three R²⁰ groups; -   R² and R³ are each independently selected from F, Cl, Br, I, OR²²,     OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆     alkynyl, C₃-C₇ cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5     or 6 membered heteroaryl, arylalkyl, C(═O)R²², CO₂R²², OC(═O)R²²,     C(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²¹CO₂R²², OC(═O)NR²³R²⁴, NR²¹C(═S)R²²,     and S(O)_(y)R²²; -   R¹⁰ and R^(10A) are each independently selected from H, C₁-C₆ alkyl,     C₆-C₁₀ aryl, C(═O)R¹⁴, and S(O)_(y)R¹⁴; wherein said alkyl and aryl     groups are optionally substituted with one to three R²⁰ groups; -   R¹¹ at each occurrence is independently selected from H, C₁-C₆     alkyl, preferably C₃-C₇ alkyl, and C₆-C₁₀ aryl; wherein said alkyl     and aryl groups are optionally substituted with one to three R²⁰     groups; -   R¹² and R¹³ at each occurrence are each independently selected from     H, C₁-C₆ alkyl, and C₆-C₁₀ aryl, or R¹² and R¹³, together with the     nitrogen to which they are attached, form a 3-7 membered     heterocyclic ring;     -   wherein said alkyl and aryl groups and heterocyclic ring are         optionally substituted with one to three R²⁰ groups; -   R¹⁴ at each occurrence is independently selected from C₁-C₆ alkyl,     C₆-C₁₀ aryl, and arylalkyl;     -   wherein said alkyl, aryl and arylalkyl groups are optionally         substituted with one to three R²⁰ groups; -   R²⁰ at each occurrence is independently selected from F, Cl, Br, I,     OR²², OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl optionally     substituted by one to three OH, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇     cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5 or 6 membered     heteroaryl, arylalkyl, ═O, C(═O)R²², CO₂R²², OC(═O)R²²,     C(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²¹CO₂R²², OC(═O)NR²³R²⁴, and     S(O)_(y)R²²; -   R²¹ at each occurrence is independently selected from H and C₁-C₆     alkyl; -   R²² at each occurrence is independently selected from H, C₁-C₆     alkyl, and C₆-C₁₀ aryl; -   R²³ and R²⁴ at each occurrence are each independently selected from     H, C₁-C₆ alkyl, and C₆-C₁₀ aryl, or R²³ and R²⁴, together with the     nitrogen to which they are attached, form a 3-7 membered     heterocyclic ring; -   R²⁵ at each occurrence is independently the residue of an amino acid     after the hydroxyl group of the carboxyl group is removed; -   m is 0 or 1; -   n is 0 or 1; -   q is 0, 1, or 2; -   y is 0, 1, or 2;     with the exclusion of the compounds wherein:     -   Y is C₂ alkylene substituted with one to three C₁-C₆ alkylene         and/or NR²³R²⁴ and/or NR²¹CO₂R²²; and     -   R¹ is C(═O)NR¹²R¹³;     -   or     -   Y is C₂ alkylene substituted with one to three (C₁-C₆) alkyl;         and     -   R¹ is phenyl optionally substituted with one to three groups         R²⁰;     -   or     -   Y is CH₂—Z—(CH₂)_(n) wherein n=0 or 1, and Z is cyclopropyl or         cyclobutyl optionally substituted; and     -   R¹ is H or phenyl optionally substituted with one to three         groups R²⁰;     -   or     -   Y is CH₂; and     -   R¹ is phenyl optionally substituted with one to three groups         R²⁰;     -   or     -   Ar is a 5-10 membered heteroaryl group or a phenyl optionally         substituted with one to three groups selected from CF₃,         NR²¹C(═O)R²², NO₂ or CO₂H; and/or     -   X is S(O)_(y); and     -   Y═CH₂ or CH₂CH₂; and     -   R¹ is H.         and with the exclusion of the compounds:     -   N-[2,6-bis(1-methylethyl)phenyl]-2-[[4-(2-pyridinylmethoxy)phenyl]methyl]thio]-acetamide;     -   tetrahydro-2-[[{4-(phenylthio)phenyl]methyl}thio]acetyl]-2H-1,2-oxazine;         and     -   2-chloro-1-[3-[(methylsulfonyl)methyl]-4-nitrophenoxy]-4-(trifluoromethyl)benzene         and the stereoisomeric forms, mixtures of stereoisomeric forms         or pharmaceutically acceptable salts forms thereof.

In a second embodiment, the present invention provides a compound of formula (I),

wherein:

-   Ar is independently selected from C₆-C₁₀ aryl and 5 to 10-membered     heteroaryl wherein:     -   C₆-C₁₀ aryl and heteroaryl are optionally substituted with one         to three groups selected from F, Cl, Br, I, OR²², OR²⁵, NR²³R²⁴,         NHOH, NO₂, CN, CF₃, C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,         C₃-C₇ cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5 or 6         membered heteroaryl, arylalkyl, C(═O)R²², CO₂R²², OC(═O)R²²,         C(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²¹CO₂R²², OC(═O)NR²³R²⁴,         NR²¹C(═S)R²², and S(O)_(y)R²²; -   X is O, S(O)_(y), N(R¹⁰), OC(R²²)₂, C(R²²)₂O, C(R²²)₂NR²¹,     NR²¹C(R²²)₂, C(═O)N(R²¹), NR²¹C(═O), S(O)₂NR²², NR²²S(O)₂,     C(R²²)₂C(R²²)₂, CR²¹═CR²¹, C≡C; -   Y is C₁-C₆alkylene;     -   (C₁-C₄ alkylene)_(m)-Z¹—(C₁-C₄ alkylene)_(n);     -   C₁-C₄ alkylene-Z²—C₁-C₄ alkylene;         -   wherein said alkylene groups are optionally substituted with             one to three R²⁰ groups; -   Z¹ is CR²¹═CR²¹, C≡C, C₆-C₁₀arylene, 5-10 membered heteroarylene,     C₃-C₆ cycloalkylene, or 3-6 membered heterocycloalkylene; wherein     said arylene, heteroarylene, cycloalkylene, and heterocycloalkylene     groups are optionally substituted with one to three R²⁰ groups; -   Z² is O, NR^(10A), or S(O)_(y); -   R¹ is selected from H, C₆-C₁₀aryl, NR¹²R¹³, NR²¹C(═O)R¹⁴, C(═O)R¹⁴,     CO₂R¹¹, OC(═O)R¹¹, C(═O)NR¹²R¹³, C(═NR¹¹)NR¹²R¹³, OC(═O)NR¹²R¹³,     NR²¹S(O)₂R¹¹, NR²¹C(═O)NR¹²R¹³, and NR²¹S(O)₂NR¹²R¹³;     -   wherein said aryl groups are optionally substituted with one to         three R²⁰ groups; -   R² and R³ are each independently selected from F, Cl, Br, I, OR²²,     OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆     alkynyl, C₃-C₇ cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5     or 6 membered heteroaryl, arylalkyl, C(═O)R²², CO₂R²², OC(═O)R²²,     C(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²¹CO₂R²²; OC(═O)NR²³R²⁴, NR²¹C(═S)R²²,     and S(O)_(y)R²²; -   R¹⁰ and R^(10A) are each independently selected from H, C₁-C₆ alkyl,     C₆-C₁₀ aryl, C(═O)R¹⁴, and S(O)_(y)R¹⁴; wherein said alkyl and aryl     groups are optionally substituted with one to three R²⁰ groups; -   R¹¹ at each occurrence is independently selected from H, C₁-C₆     alkyl, and C₆-C₁₀ aryl;     -   wherein said alkyl and aryl groups are optionally substituted         with one to three R²⁰ groups; -   R¹² and R¹³ at each occurrence are each independently selected from     H, C₁-C₆ alkyl, and C₆-C₁₀ aryl, or R¹² and R¹³, together with the     nitrogen to which they are attached, form a 3-7 membered     heterocyclic ring;     -   wherein said alkyl and aryl groups and heterocyclic ring are         optionally substituted with one to three R²⁰ groups; -   R¹⁴ at each occurrence is independently selected from C₁-C₆ alkyl,     C₆-C₁₀ aryl, and arylalkyl;     -   wherein said alkyl, aryl and arylalkyl groups are optionally         substituted with one to three R²⁰ groups; -   R²⁰ at each occurrence is independently selected from F, Cl, Br, I,     OR²², OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl optionally     substituted by one to three OH, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇     cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5 or 6 membered     heteroaryl, arylalkyl, ═O, C(═O)R²², CO₂R²², OC(═O)R²²,     C(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²¹CO₂R²², OC(═O)NR²³R²⁴, NR²¹C(═S)R²²,     and S(O)_(y)R²²; -   R²¹ at each occurrence is independently selected from H and C₁-C₆     alkyl; -   R²² at each occurrence is independently selected from H, C₁-C₆     alkyl, and C₆-C₁₀ aryl; -   R²³ and R²⁴ at each occurrence are each independently selected from     H, C₁-C₆ alkyl, and C₆-C₁₀ aryl, or R²³ and R²⁴, together with the     nitrogen to which they are attached, form a 3-7 membered     heterocyclic ring; -   R²⁵ at each occurrence is independently the residue of an amino acid     after the hydroxyl group of the carboxyl group is removed; -   m is 0 or 1; -   n is 0 or 1; -   q is 0, 1, or 2; -   y is 0, 1, or 2;     and the stereoisomeric forms, mixtures of stereoisomeric forms or     pharmaceutically acceptable salts forms thereof.

In another preferred embodiment of the invention, there are provided compounds of formula (Ia)

wherein:

-   Ar is independently selected from C₆-C₁₀ aryl and 5 to 10-membered     heteroaryl, wherein:     -   C₆-C₁₀ aryl and heteroaryl are optionally substituted with one         to three groups selected from F, Cl, Br, I, OR²², OR²⁵, NR²³R²⁴,         NHOH, NO₂, CN, C₁-C₆ alkyl, phenyl, arylalkyl, and C(═O)R²²; -   X is O, S(O)_(y), N(R¹⁰), OC(R²²)₂, C(R²²)₂O, C(R²²)₂NR²¹,     NR²¹C(R²²)₂, C(═O)N(R²¹), NR²¹C(═O), S(O)₂NR²², NR²²S(O)₂; -   Y is C₁-C₆alkylene;     -   C₁-C₄ alkylene-Z¹—(C₁-C₄ alkylene)_(n); or     -   C₁-C₄ alkylene-Z²—C₁-C₄ alkylene;     -   wherein said alkylene groups are optionally substituted with one         to three R²⁰ groups; -   Z¹ is CR²¹═CR²¹, C≡C, C₆-C₁₀ arylene, 5-10 membered heteroarylene,     C₃-C₆ cycloalkylene, or 3-6 membered heterocycloalkylene; -   Z² is O, NR^(10A), or S(O)_(y); -   R¹ is selected from NR²¹C(═O)R¹⁴, C(═O)R¹⁴, CO₂R¹¹, OC(═O)R¹¹,     C(═O)NR¹²R¹³, C(═NR¹¹)NR¹²R¹³, OC(═O)NR¹²R¹³, NR²¹S(O)₂R¹¹,     NR²¹C(═O)NR¹²R¹³, and NR²¹S(O)₂NR¹²R¹³; -   R² and R³ are each independently selected from F, Cl, Br, I, OR²²,     OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl, phenyl, 5 or 6     membered heteroaryl, arylalkyl, C(═O)R²²; -   R¹⁰ and R^(10A) are each independently selected from H, C₁-C₆ alkyl,     C(═O)R¹⁴, and S(O)_(y)R¹⁴;     -   wherein said alkyl groups are optionally substituted with one to         three R²⁰ groups; -   R¹¹ at each occurrence is independently selected from H, and C₁-C₆     alkyl; wherein said alkyl groups are optionally substituted with one     to three R²⁰ groups; -   R¹² and R¹³ at each occurrence are each independently selected from     H, and C₁-C₆ alkyl, or R¹² and R¹³, together with the nitrogen to     which they are attached, form a 3-7 membered heterocyclic ring;     -   wherein said alkyl and aryl groups and heterocyclic ring are         optionally substituted with one to three R²⁰ groups; -   R¹⁴ at each occurrence is independently selected from C₁-C₆ alkyl,     C₆-C₁₀ aryl, and arylalkyl;     -   wherein said alkyl, aryl and arylalkyl groups are optionally         substituted with one to three R²⁰ groups; -   R²⁰ at each occurrence is independently selected from F, Cl, Br, I,     OR²², OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, phenyl, benzyl, ═O,     C(═O)R²², CO₂R²², OC(═O)R²², C(═O)NR²³R²⁴, NR²¹CO₂R²²,     OC(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²¹C(═S)R²², and S(O)_(y)R²²; -   R²¹ at each occurrence is independently selected from H and C₁-C₆     alkyl; -   R²² at each occurrence is independently selected from H, C₁-C₆     alkyl, and C₆-C₁₀ aryl; -   R²³ and R²⁴ at each occurrence are each independently selected from     H, and C₁-C₆ alkyl, or R²³ and R²⁴, together with the nitrogen to     which they are attached, form a 3-7 membered heterocyclic ring; -   R²⁵ at each occurrence is independently the residue of an amino acid     after the hydroxyl group of the carboxyl group is removed; -   n is 0 or 1; -   y is 0, 1, or 2;     and the stereoisomeric forms, mixtures of stereoisomeric forms or     pharmaceutically acceptable salts forms thereof.

An additional aspect of the present invention includes compounds of formula (A) and formulas (I) and (Ia) wherein Y is C₁-C₆ alkylene, C₁-C₄ alkylene-Z¹—C₁-C₄ alkylene, or C₁-C₄ alkylene-Z²—C₁-C₄ alkylene, wherein said alkylene groups are optionally substituted with one to three C₁-C₆ alkyl groups; Z¹ is CR²¹═CR²¹, C≡C, or phenyl; Z is O, NR^(10A), or S(O)_(y); R¹ is selected from NR²¹C(═O)R¹⁴, C(═O)R¹⁴, CO₂R¹¹, OC(═O)R¹¹, and C(═O)NR¹²R¹³. In other aspects, Y is C₁-C₆ alkylene, or C₁-C₄ alkylene-Z¹—C₁-C₄ alkylene. In additional aspects, Y is C₁-C₆ alkylene. In further aspects, R¹ is C(═O)NR¹²R¹³.

In certain aspects of the present invention, there are included compounds of formula (A) and formulas (I) and (Ia) where Ar is phenyl. Other aspects include compounds where Ar is napthyl. Other aspects include compounds where Ar is thienyl. Other aspects include compounds where Ar is furyl.

In additional aspects of the present invention, there are included compounds of formula (A) and formulas (I) and (Ia) wherein Ar has any of the values of the previous embodiments and q is 1.

In other aspects of the present invention, there are included compounds of formula (A) and formulas (I) and (Ia) where X is O, S(O)_(y), N(R¹⁰), OC(R²²)₂, C(R²²)₂NR²¹, C(═O)N(R²¹), S(O)₂NR²².

In additional aspects of the present invention, there are included compounds of formula (A) and formulas (I) and (Ia) where X is O, S(O)_(y), N(R¹⁰), OC(R²²)₂, C(R²²)₂NR²¹, C(═O)N(R²¹), S(O)₂NR²² and q is 1.

Other aspects of the present invention include compounds of formula (A) and formulas (I) and (Ia) wherein Ar and X and q have any of the values of the previous embodiments, and Y is C₁-C₆ alkylene, particularly those where Y is CH₂ or CH₂CH₂, and most particularly those where Y is CH₂.

Additional aspects of the present invention include compounds of formula (A) and formulas (I) and (Ia) wherein Ar, X and q have any of the values of the previous embodiments, and Y is (C₁-C₄ alkylene)_(m)-Z¹—(C₁-C₄ alkylene), wherein Z¹ is CR²¹═CR²¹, C≡C, C₆-C₁₀ arylene, 5-10 membered heteroarylene, C₃-C₆ cycloalkylene, or 3-6 membered heterocycloalkylene. Other aspects include those compounds where Y is C₁-C₄ alkylene-Z¹. Other aspects include those where Y is Z¹—C₁-C₄ alkylene. Additional aspects include compounds where Y is C₁-C₄ alkylene-Z¹—C₁-C₄ alkylene.

Further aspects of the present invention include compounds of formula (A) and formulas (I) and (Ia) wherein Ar, X, Y, and q have any of the values of the previous embodiments, and Z¹ is CR²¹═CR²¹, or C≡C. Other aspects include compounds where Z¹ is C₆-C₁₀ arylene, or C₃-C₆ cycloalkylene, particularly those where Z¹ is phenyl. Other aspects include compounds where Z¹ is 5-10 membered heteroarylene, or 3-6 membered heterocycloalkylene.

Further aspects of the present invention include compounds of formula (A) and formulas (I) and (Ia) wherein Ar, X and q have any of the values of the previous embodiments, and Y is (C₁-C₄ alkylene)_(m)-Z²—(C₁-C₄ alkylene)_(n) wherein Z² is O, NR^(10A), or S(O)_(y). Other aspects include those compounds where Y is C₁-C₄ alkylene-Z², wherein R¹ cannot be H. Other aspects include those compounds where Y is C₁-C₄ alkylene-Z²—C₁-C₄ alkylene. Additional aspects include any of the above embodiments of Y wherein Z² is O. Additional aspects include any of the above embodiments of Y wherein Z² is NR^(10A).

Further aspects of the present invention include compounds of formula (A) and formulas (I) and (Ia) wherein Ar, Y, Z¹, and Z², and q have any of the values of the previous embodiments, and R¹ can be any value selected from the following 12 enumerated paragraphs:

-   -   1. H.     -   2. NR¹²R¹³.     -   3. NR²¹C(═O)R¹⁴.     -   4. C(═O)R¹⁴.     -   5. CO₂R¹¹.     -   6. OC(═O)R¹¹.     -   7. C(═O)NR¹²R¹³.     -   8. C(═NR¹¹)NR¹²R¹³.     -   9. OC(═O)NR¹²R¹³.     -   10. NR²¹S(O)₂R¹¹.     -   11. NR²¹C(═O)NR¹²R¹³.     -   12. NR²¹S(O)₂NR¹²R¹³.

Other additional aspects of the present invention include compounds of formula (A) and formulas (I) and (Ia) wherein Ar, Y, Z¹, and Z², and q have any of the values of the previous embodiments, and R¹ can be a combination of the values selected from the previous 12 enumerated paragraphs. The preceding 12 enumerated paragraphs may be combined to further define additional preferred embodiments of compounds of the present invention. For example, one such combination includes NR¹²R¹³, NR²¹C(═O)R¹⁴, C(═O)R¹⁴, CO₂R¹¹, OC(═O)R¹¹, C(═O)NR¹²R¹³, C(═NR¹¹)NR¹²R¹³, OC(═O)NR¹²R¹³, NR²¹S(O)₂R¹¹, NR²¹C(═O)NR¹²R¹³, and NR²¹S(O)₂NR¹²R¹³.

Another such combination includes NR¹²R¹³, wherein R¹² and R¹³ are each independently selected from H and C₁-C₆ alkyl; NR²¹C(═O)R¹⁴; C(═O)NR¹²R¹³; C(═NR¹¹)NR¹²R¹³; and NR²¹C(═O)NR¹²R¹³.

A third such combination includes C(═O)R¹⁴, CO₂R¹¹, OC(═O)R¹¹, C(═O)NR¹²R¹³; C(═O)NR¹²R¹³, NR²¹S(O)₂R¹¹, and NR²¹S(O)₂NR¹²R¹³.

A fourth such combination includes NR²¹C(═O)R¹⁴, C(═O)R¹⁴, CO₂R¹¹, OC(═O)R¹¹, and C(═O)NR¹²R¹³.

A fifth such combination includes NR²¹C(═O)R¹⁴ and C(═O)NR¹²R¹³.

In still further aspects of the present invention, there are included compounds of formula (Ib):

wherein Ar, X and Y have any of the values of the previous embodiments.

Additional aspects of the present invention include compounds of formula (A) and formulas (I), (Ia) and (Ib) wherein Ar, X, y, Z¹, Z², R¹, and q have any of the values of the previous embodiments, and R¹² and R¹³ are each independently selected from H and C₁-C₆ alkyl.

Other aspects of the present invention include compounds of formula (A) and formulas (I), (Ia) and (Ib) wherein Ar, Y, Z¹, Z², R¹, and q have any of the values of the previous embodiments, and R¹² and R¹³ together with the nitrogen to which they are attached, form a 3-7 membered heterocyclic ring, particularly those where the heterocyclic ring is a heterocycloalkyl group, and more particularly those where the heterocyclic group is pyrrolidine or piperidine. In certain aspects, the heterocyclic ring is substituted with one R²⁰. In other aspects, the heterocyclic ring is unsubstituted.

Other aspects of the present invention include compounds of formula (A) and formulas (I), (Ia) and (Ib), wherein Y is C₁-C₆ alkylene and/or R¹ is selected from NR¹²R¹³, NR²¹C(═O)R¹⁴, C(═O)R¹⁴, CO₂R¹¹, OC(═O)R¹¹, C(═O)NR¹²R¹³, C(═NR¹¹)NR¹²R¹³, OC(═O)NR¹²R¹³, NR²¹S(O)₂R¹¹, NR²¹C(═O)NR¹²R¹³, and NR²¹S(O)₂NR¹²R¹³.

In accordance with a preferred embodiment, Ar is a C₆-C₁₀ aryl, more preferably phenyl or naphtyl.

In accordance with another preferred embodiment, Ar is a 5-10 membered heteroaryl, notably a 5 or 6 membered heteroaryl such as thienyl or furyl.

Ar is optionally substituted with one to three groups, preferably selected from halogen atoms (F, Cl, Br, I), OR²², or phenyl.

In that context, the following Ar substituents are particularly preferred.

Preferably, halogen atoms are Cl and F.

Preferably, OR²² is O(C₁-C₆) alkyl such as O-methyl, O-ethyl, O-isopropyl.

In accordance with a preferred embodiment, X is O, S(O)_(y), N(R¹⁰), OC(R²²)₂, C(R²²)₂O, C(R²²)₂NR²¹, NR²¹C(R²²)₂, C(═O)N(R²¹), NR²¹C(═O), S(O)₂NR²², NR²²S(O)₂.

Preferably, X is O, S(O)_(y), NH, OCH₂, CH₂O, CH₂NH, NHCH₂, C(═O)NH, NHC(═O), S(O)₂NH, NHS(O)₂, more preferably O, S, SO, NH, OCH₂, CH₂NH, C(═O)NH, S(O)₂NH.

In accordance with a preferred embodiment Y is (C₁-C₆) alkylene, preferably unsubstituted (C₁-C₆) alkylene and more preferably CH₂.

In accordance with a preferred embodiment, R¹ is selected from H, CO₂R¹¹, C(═O)NR¹²R¹³, and is more preferably a C(═O)NR¹²R¹²R¹³.

Preferably, R¹² and R¹³, at each occurrence are each independently selected from H, C₁-C₆ alkyl, or R¹² and R¹³ together with the nitrogen to which they are attached, form a 3-7 membered heterocyclic ring.

According to a preferred embodiment R¹² and R¹³ together with the nitrogen to which they are attached, form a 3-7 membered heterocyclic ring, more preferably a 5-6 membered heterocyclic ring.

Preferably, the heterocyclic ring is a cycloalkyl group in which one or more ring atoms, more preferably one or two, are replaced by —N—.

Preferably, the heterocyclic ring is selected from the group consisting of pyrrolidinyl, piperidyl and piperazinyl.

The heterocyclic ring may be substituted with one to three R²⁰ groups, preferably independently selected from C₁-C₆ alkyl optionally substituted with one to three OH, C(═O)R²², CO₂R²², C(═O)NR²³R²⁴.

Examples of R²⁰ representing a C(═O)R²² group are notably the groups wherein R²² represents a C₁-C₆ alkyl group such as acetyl (C(═O)CH₃), or ethylcarbonyl (C(═O)CH₂CH₃).

Examples of R²⁰ representing a CO₂R²² group are notably CO₂R²² wherein R²² is H or C₁-C₆ alkyl such as ter-butoxycarbonyl (Boc)(CO₂(tBu)).

Examples of R²⁰ representing a C₁-C₆ alkyl group optionally substituted with one to three OH are notably hydroxyethyl.

In accordance with another preferred embodiment, R¹² and R¹³, at each occurrence are each independently selected from H or C₁-C₆ alkyl.

Examples of R¹², R¹³ representing a C₁-C₆ alkyl group are notably methyl, ethyl, t-butyl, optionally substituted with one to three R²⁰ groups, notably OH or CN.

Examples of C(═O)NR¹²R¹³ wherein R¹² and R¹³ are each independently selected from H or C₁-C₆ alkyl are notably C(═O)NH₂ or C(═O)NMe₂, C(═O)NH(CH₂)₂OH, C(═O)NHCMe₃.

In a preferred embodiment of the present invention there are provided compounds of formula (A) and formula (I):

wherein Ar, X, R² and R³, q, Y—R¹ are defined in the Table 1 below.

In Table 1, the term “position” refers to the position of the Ar—X lateral side chain as compared to —CH₂—S(O)q-Y—R¹ group on the central benzyl ring.

In addition, the positions of substituents on the Ar group and on the central core phenyl group are numbered as follows:

TABLE 1

Ex. n^(o) Ar X Position* R² R³ q Y—R¹ 13 3,4-DiClPh O para H H 0 CH₂CO—N- piperazinyl-N—Boc 14 3,4-DiClPh O para H H 0 CH₂CO—N-piperazinyl 19 3,4-DiClPh O para H H 1 CH₂CO—N-piperazinyl 16 4-ClPh S para H H 0 CH₂CO-1-(4-acetyl)- piperazinyl 23 4-ClPh S para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 24 4-ClPh SO para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 29 Ph O para H H 1 CH₂CONHCHMe₂ Ph O meta H H 0 CH₂CO—N- pyrrolidinyl 31 Ph O meta H H 1 CH₂CO—N- pyrrolidinyl Ph O meta H H 0 CH₂CONH₂ 32 Ph O meta H H 1 CH₂CONH₂ Ph O meta H H 0 CH₂CONMe₂ 33 Ph O meta H H 1 CH₂CONMe₂ Ph O meta H H 0 CH₂CONHCHMe₂ 34 Ph O meta H H 1 CH₂CONHCHMe₂ Ph O meta H H 0 CH₂CO-1-(4-acetyl)- piperazinyl 35 Ph O meta H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 4-OCH₃Ph O para H H 0 CH₂CONH₂ 36 4-OCH₃Ph O para H H 1 CH₂CONH₂ 4-OCH₃Ph O para H H 0 CH₂CO-1-(4-acetyl)- piperazinyl 37 4-OCH₃Ph O para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 4-OCH₃Ph O para H H 0 CH₂CO—N-piperazinyl 38 4-OCH₃Ph O para H H 1 CH₂CO—N-piperazinyl 3,4-DiClPh O para H H 0 CH₂CONH₂ 39 3,4-DiClPh O para H H 1 CH₂CONH₂ 11 3,4-DiClPh O para H H 0 CH₂CO-1-(4-acetyl)- piperazinyl 22 3,4-DiClPh O para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 27 3,4-DiClPh O para H H 2 CH₂CO-1-(4-acetyl)- piperazinyl 30 3,4-DiClPh O para H H 1 CH₂COOH 15 3,4-DiClPh O ortho H H 0 CH₂CONH₂ 20 3,4-DiClPh O ortho H H 1 CH₂CONH₂ 3,4-DiClPh O ortho H H 0 CH₂CO-1-(4-acetyl)- piperazinyl 40 3,4-DiClPh O ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 3,4-DiClPh O para H H 0 CH₂CO-1-(4- carboxamide)- piperazinyl 41 3,4-DiClPh O para H H 1 CH₂CO-1-(4- carboxamide)- piperazinyl 4-OCH₃Ph O ortho H H 0 CH₂CONH₂ 42 4-OCH₃Ph O ortho H H 1 CH₂CONH₂ 2-ClPh O para H H 0 CH₂CONH₂ 43 2-ClPh O para H H 1 CH₂CONH₂ 4-OHPh O ortho H H 0 CH₂CONH₂ 44 4-OHPh O ortho H H 1 CH₂CONH₂ 2-ClPh O ortho H H 0 CH₂CONH₂ 45 2-ClPh O ortho H H 1 CH₂CONH₂ 2-ClPh O para H H 0 CH₂CO-1-(4-acetyl)- piperazinyl 46 2-ClPh O para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 2-ClPh O para H H 0 CH₂CO—N-piperazinyl 47 2-ClPh O para H H 1 CH₂CO—N-piperazinyl 4-FPh O para H H 0 CH₂CO-1-(4-acetyl)- piperazinyl 48 4-FPh O para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 95 4-FPh O para H H 2 CH₂CO-1-(4-acetyl)- piperazinyl 96 4-FPh O para H H 1 CH₂COOH 4-FPh O ortho H H 0 CH₂CO-1-(4-acetyl)- piperazinyl 49 4-FPh O ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 4-FPh O para H H 0 CH₂CONH₂ 50 4-FPh O para H H 1 CH₂CONH₂ 4-FPh O ortho H H 0 CH₂CONH₂ 51 4-FPh O ortho H H 1 CH₂CONH₂ 2-Naphthyl O ortho H H 0 CH₂CONH₂ 52 2-Naphthyl O ortho H H 1 CH₂CONH₂ 2-Naphthyl O ortho H H 0 CH₂CO-1-(4-acetyl)- piperazinyl 53 2-Naphthyl O ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 2-Naphthyl O para H H 0 CH₂CONH₂ 54 2-Naphthyl O para H H 1 CH₂CONH₂ 2-BiPh O para H H 0 CH₂CONH₂ 55 2-BiPh O para H H 1 CH₂CONH₂ 2-BiPh O ortho H H 0 CH₂CONH₂ 56 2-BiPh O ortho H H 1 CH₂CONH₂ 2ClPh O ortho H H 0 CH₂CO-1-(4-acetyl)- piperazinyl 57 2ClPh O ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 2-Naphthyl O para H H 0 CH₂CO-1-(4-acetyl)- piperazinyl 58 2-Naphthyl O para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 2-BiPh O ortho H H 0 CH₂CO-1-(4-acetyl)- piperazinyl 59 2-BiPh O ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 2-BiPh O para H H 0 CH₂CO-1-(4-acetyl)- piperazinyl 60 2-BiPh O para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 4-ClPh O para H H 0 CH₂CO-1-(4-acetyl)- piperazinyl 61 4-ClPh O para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 4-OCH₃Ph O para H H 0 CH₂CO-1-(4-methyl)- piperazinyl 62 4-OCH₃Ph O para H H 1 CH₂CO-1-(4-methyl)- piperazinyl 3,4-DiClPh O para H H 0 CH₂CO-1-(4- ethylcarboxylate)- piperazinyl 63 3,4-DiClPh O para H H 1 CH₂CO-1-(4- ethylcarboxylate)- HHpiperazinyl 4-FPh O para H H 0 CH₂CO-1-(4- hydroxyethyl)- piperazinyl 64 4-FPh O para H H 1 CH₂CO-1-(4- hydroxyethyl)- piperazinyl 3,4-DiClPh O ortho H H 0 CH₂CO-1-(4- hydroxyethyl)- piperazinyl 65 3,4-DiClPh O ortho H H 1 CH₂CO-1-(4- hydroxyethyl)- piperazinyl 4-FPh O para H H 0 CH₂CO-1-(4-methyl)- piperazinyl 66 4-FPh O para H H 1 CH₂CO-1-(4-methyl)- piperazinyl 4-ClPh O para H H 0 CH₂CONH₂ 67 4-ClPh O para H H 1 CH₂CONH₂ 4-FPh O para H H 0 CH₂CO-1-(4- ethylcarboxylate)- piperazinyl 68 4-FPh O para H H 1 CH₂CO-1-(4- ethylcarboxylate)- piperazinyl 4-OCH₃Ph O para H H 0 CH₂CO-1-(4- etbylcarboxylate)- piperazinyl 69 4-OCH₃Ph O para H H 1 CH₂CO-1-(4- ethylcarboxylate)- piperazinyl 4-ClPh S para H H 0 CH₂CO-1-(4- ethylcarboxylate)- piperazinyl 70 4-ClPh S para H H 1 CH₂CO-1-(4- ethylcarboxylate)- piperazinyl 71 4-ClPh SO para H H 1 CH₂CO-1-(4- ethylcarboxylate)- piperazinyl 3,4-DiClPh O ortho H H 0 CH₂CO-1-(4- ethylcarboxylate)- piperazinyl 72 3,4-DiClPh O ortho H H 1 CH₂CO-1-(4- ethylcarboxylate)- piperazinyl Ph O ortho H H 0 CH₂CONH₂ 97 Ph O ortho H H 1 CH₂CONH₂ Ph O ortho H H 0 CH₂CO—N- pyrrolidinyl 98 Ph O ortho H H 1 CH₂CO—N- pyrrolidinyl Ph O ortho H H 0 CH₂CONMe₂ 99 Ph O ortho H H 1 CH₂CONMe₂ Ph O para H H 0 CH₂CONMe₂ 100 Ph O para H H 1 CH₂CONMe₂ Ph O para H H 0 CH₂CO—N- pyrrolidinyl 101 Ph O para H H 1 CH₂CO—N- pyrrolidinyl Ph O para H H 0 CH₂CONH₂ 102 Ph O para H H 1 CH₂CONH₂ Ph O ortho H H 0 CH₂CONHCH₂CN 103 Ph O ortho H H 1 CH₂CONHCH₂CN Ph O ortho H H 0 CH₂CONHCHMe₂ 104 Ph O ortho H H 1 CH₂CONHCHMe₂ Ph O ortho H H 0 CH₂CONHCMe₃ 105 Ph O ortho H H 1 CH₂CONHCMe₃ Ph O ortho H H 0 CH₂CO-1-(4- hydroxy)-piperidinyl 106 Ph O ortho H H 1 CH₂CO-1-(4- hydroxy)-piperidinyl 12 Ph O ortho H H 0 CH₂CONH(CH₂)₂OH 21 Ph O ortho H H 1 CH₂CONH(CH₂)₂OH Ph O ortho H H 0 CH₂CO-1-(4-acetyl)- piperazinyl 107 Ph O ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl Ph O meta H H 0 CH₂CONH(CH₂)₂OH 108 Ph O meta H H 1 CH₂CONH(CH₂)₂OH Ph O meta H H 0 CH₂CO-1-(4- hydroxy)-piperidinyl 109 Ph O meta H H 1 CH₂CO-1-(4- hydroxy)-piperidinyl 110 Ph O para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 111 Ph O para H H 1 CH₂CONH(CH₂)₂OH 112 Ph O para H H 1 CH₂CO-1-(4- hydroxy)-piperidinyl 113 4-ClPh CONH ortho H H 1 CH₂CONH₂ 114 3,4-DiOCH₃Ph CONH ortho H H 1 CH₂CONH₂ 115 2-Naphthyl CONH ortho H H 1 CH₂CONH₂ 116 4-ClPh CONH ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 117 3,4DiFPh CONH ortho H H 1 CH₂CONH₂ 118 2,4-DiOCH₃Ph CONH ortho H H 1 CH₂CONH₂ 119 3,4,5- CONH ortho H H 1 CH₂CONH₂ TriOCH₃Ph 120 3,4-DiOCH₃Ph CONH meta H H 1 CH₂CONH₂ 121 2,4-DiOCH₃Ph CONH ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 122 3,4-DiOCH₃Ph CONH ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 123 4-FPh CONH ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 124 3,4-DiClPh CONH ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 125 2,4-DiOCH₃Ph CONH meta H H 1 CH₂CONH₂ 126 4-FPh CONH meta H H 1 CH₂CONH₂ 127 3,4-DiClPh CONH meta H H 1 CH₂CONH₂ 7 4-ClPh O para H H 0 CH₃ 8 4-ClPh O para H H 1 CH₃ 9 4-ClPh O para H H 1 CH₂[4(4- ClPhenoxy)phenyl] 3,4-DiClPh O para H H 0 CH₃ 10 3,4-DiClPh O para H H 1 CH₃ 4-ClPh S ortho H H 0 CH₂CO—N-piperazinyl 73 4-ClPh S ortho H H 1 CH₂CO—N-piperazinyl 2,3-DiClPh O ortho H H 0 CH₂CO-1-(4-acetyl)- piperazinyl 74 2,3-DiClPh O ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 2,5-DiClPh O ortho H H 0 CH₂CO-1-(4-acetyl)- piperazinyl 75 2,5-DiClPh O ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 2,5-DiClPh O ortho H H 0 CH₂CONH₂ 76 2,5-DiClPh O ortho H H 1 CH₂CONH₂ 2,3-DiClPh O ortho H H 0 CH₂CONH₂ 77 2,3-DiClPh O ortho H H 1 CH₂CONH₂ 2,4-DiClPh O para H H 0 CH₂CO-1-(4-acetyl)- piperazinyl 78 2,4-DiClPh O para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 2,4-DiClPh O ortho H H 0 CH₂CO-1-(4-acetyl)- piperazinyl 79 2,4-DiClPh O ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 2,4-DiClPh O para H H 0 CH₂CONH₂ 80 2,4-DiClPh O para H H 1 CH₂CONH₂ 2,4-DiClPh O ortho H H 0 CH₂CONH₂ 81 2,4-DiClPh O ortho H H 1 CH₂CONH₂ 3,5-DiClPh O ortho H H 0 CH₂CO-1-(4-acetyl)- piperazinyl 82 3,5-DiClPh O ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 3,5-DiClPh O para H H 0 CH₂CO-1-(4-acetyl)- piperazinyl 83 3,5-DiClPh O para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 3,5-DiClPh O para H H 0 CH₂CONH₂ 84 3,5-DiClPh O para H H 1 CH₂CONH₂ 3,5-DiClPh O ortho H H 0 CH₂CONH₂ 85 3,5-DiClPh O ortho H H 1 CH₂CONH₂ 2,5-DiClPh O para H H 0 CH₂CO-1-(4-acetyl)- piperazinyl 86 2,5-DiClPh O para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 3,4-DiClPh S para H H 0 CH₂CO-1-(4-acetyl)- piperazinyl 87 3,4-DiClPh S para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 2,5-DiClPh S para H H 0 CH₂CONH₂ 88 2,5-DiClPh S para H H 1 CH₂CONH₂ 3,4-DiClPh S para H H 0 CH₂CONH₂ 89 3,4-DiClPh S para H H 1 CH₂CONH₂ 2,3-DiClPh O para H H 0 CH₂CO-1-(4-acetyl)- piperazinyl 90 2,3-DiClPh O para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 2,6-DiClPh O para H H 0 CH₂CO-1-(4-acetyl)- piperazinyl 91 2,6-DiClPh O para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 2,6-DiClPh O para H H 0 CH₂CONH₂ 92 2,6-DiClPh O para H H 1 CH₂CONH₂ 2,3-DiClPh O para H H 0 CH₂CONH₂ 93 2,3-DiClPh O para H H 1 CH₂CONH₂ 94 2,3-DiClPh O para H H 2 CH₂CONH₂ 135 Ph NH ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 136 Ph NH para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 134 4-OCH₃Ph NH ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 131 4-FPh SO₂NH para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 137 4-OCH₃Ph NH para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 138 4-FPh NH para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 139 4-ClPh NH para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 140 4-FPh NH para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 128 3,4-DiClPh CONH para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 129 4-FPh CONH para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 141 3,4-DiClPh NH para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 132 4-ClPh SO₂NH para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 147 4-FPh CH₂NH para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 133 3,4-DiClPh SO₂NH para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 148 3,4-DiClPh CH₂NH para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 149 4-FPh CH₂NH ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 146 3,4-DiClPh CH₂NH ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 130 3,4-DiClPh SO₂NH ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 145 2-Furyl CH₂NH ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 144 2-Thienyl CH₂NH ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 142 2-Thienyl CONH ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 143 2-Furyl CONH ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 152 Ph OCH₂ ortho H H 0 CH₂CONH₂ 153 Ph OCH₂ ortho H H 1 CH₂CONH₂ 17 4-ClPh O para 2′-Cl H 0 CH₂CO-1-(4-acetyl)- piperazinyl 18 4-ClPh O para 2′-Cl H 0 CH₂CONH₂ 25 4-ClPh O para 2′-Cl H 1 CH₂CO-1-(4-acetyl)- piperazinyl 26 4-ClPh O para 2′-Cl H 1 CH₂CONH₂  149a 3,4-DiClPh CONH para H H 1 CH₂CONH₂  109a 4-ClPh O ortho H H 1 CH₂CONH₂  109b 3-Cl-4-FPh O ortho H H 1 CH₂CONH₂  109c 4-Cl-3-FPh O ortho H H 1 CH₂CONH₂  109d 3-Cl-4-FPh O ortho H H 2 CH₂CONH₂   10a 4-ClPh O ortho 4′-Cl H 0 CH₂COOH   18a 4-ClPh O ortho 4′-Cl H 0 CH₂CONH₂   27a 4-ClPh O ortho 4′-Cl H 1 CH₂CONH₂  27b 4-ClPh O ortho 4′-Cl H 2 CH₂CONH₂  109e 3,4-DiFPh O ortho 4′-Cl H 1 CH₂CONH₂   109f 3,4-DiClPh O ortho H H 2 CH₂CONH₂   30a 3,4-DiClPh O ortho H H 1 CH₂COOH  30d 3,4-DiClPh O ortho H H 0 CH₂COOMenthyl (1R,2S,5R)   30e 3,4-DiClPh O ortho H H 1 CH₂COOH (−)    30f 3,4-DiClPh O ortho H H 1 CH₂COOH (+)   20a 3,4-DiClPh O ortho H H 1 CH₂CONH₂ (−)  20b 3,4-DiClPh O ortho H H 1 CH₂CONH₂ (+)  30b 3,4-DiClPh O ortho H H 2 CH₂COOH  112a 3,4-DiClPh O ortho H H 1 CH₂CONHCH₃  112b 3,4-DiClPh O ortho H H 1 CH₂CON(C₂H₅)₂    30f 3,4-DiClPh O ortho H H 0 CH₂CON(CH₃)₂  30g 3,4-DiClPh O ortho H H 1 CH₂CON(CH₃)₂ Ph = phenyl, ClPh = chlorophenyl, DiClPh = di-chlorophenyl, FPh = Fluoprophenyl. *Position: Ortho is position 2′, meta is position 3′ and para is position 4′.

In a second embodiment, the present invention provides a method for treatment of diseases comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (A) and formula (I), or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the present invention is to provide methods of treating or preventing diseases or disorders, including treatment of sleepiness, promotion and/or improvement of wakefulness, preferably improvement of wakefulness in patients with excessive sleepiness associated with narcolepsy, sleep apnea, preferably obstructive sleep apnea/hypopnea, and shift work disorder; treatment of Parkinson's disease; Alzheimer's disease; cerebral ischemia; stroke; eating disorders; attention deficit disorder (“ADD”), attention deficit hyperactivity disorder (“ADHD”); depression; schizophrenia; fatigue, preferably fatigue associated with cancer or neurological diseases, such as multiple sclerosis and chronic fatigue syndrome; stimulation of appetite and weight gain and improvement of cognitive dysfunction.

In a third embodiment, the present invention provides a pharmaceutical compositions comprising the compounds of formula (A) and formula (I) wherein the compositions comprise one or more pharmaceutically acceptable excipients and a therapeutically effective amount of at least one of the compounds of the present invention, or a pharmaceutically acceptable salt or ester form thereof.

In a fourth embodiment, the present invention provides for the use of compounds of formula (A) and formula (I) or pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment of a disease or disorder.

These and other objects, features and advantages of the benzyl-thioalkyl derivatives will be disclosed in the following detailed description of the patent disclosure.

DEFINITIONS

The following terms and expressions contained herein are defined as follows:

As used herein, the term “about” refers to a range of values from ±10% of a specified value. For example, the phrase “about 50 mg” includes ±10% of 50, or from 45 to 55 mg.

As used herein, a range of values in the form “x-y” or “x to y”, or “x through y”, include integers x, y, and the integers therebetween. For example, the phrases “1-6”, or “1 to 6” or “1 through 6” are intended to include the integers 1, 2, 3, 4, 5, and 6. Preferred embodiments include each individual integer in the range, as well as any subcombination of integers. For example, preferred integers for “1-6” can include 1, 2, 3, 4, 5, 6, 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, 2-5, 2-6, etc.

As used herein “stable compound” or “stable structure” refers to a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and preferably capable of formulation into an efficacious therapeutic agent. The present invention is directed only to stable compounds.

As used herein, the term “alkyl” refers to a straight-chain, or branched alkyl group having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, neopentyl, 1-ethylpropyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, hexyl, octyl, etc. The alkyl moiety of alkyl-containing groups, such as alkoxy, alkoxycarbonyl, and alkylaminocarbonyl groups, has the same meaning as alkyl defined above. Lower alkyl groups, which are preferred, are alkyl groups as defined above which contain 1 to 4 carbons. A designation such as “C₁-C₄ alkyl” refers to an alkyl radical containing from 1 to 4 carbon atoms.

As used herein, the term “alkenyl” refers to a straight chain, or branched hydrocarbon chains of 2 to 8 carbon atoms having at least one carbon-carbon double bond. A designation “C₂-C₈ alkenyl” refers to an alkenyl radical containing from 2 to 8 carbon atoms. Examples of alkenyl groups include ethenyl, propenyl, isopropenyl, 2,4-pentadienyl, etc.

As used herein, the term “alkynyl” refers to a straight chain, or branched hydrocarbon chains of 2 to 8 carbon atoms having at least one carbon-carbon triple bond. A designation “C₂-C₈ alkynyl” refers to an alkynyl radical containing from 2 to 8 carbon atoms. Examples include ethynyl, propynyl, isopropynyl, 3,5-hexadiynyl, etc.

As used herein, the term “alkylene” refers to a substituted or unsubstituted, branched or straight chained hydrocarbon of 1 to 8 carbon atoms, which is formed by the removal of two hydrogen atoms. A designation such as “C₁-C₄ alkylene” refers to an alkylene radical containing from 1 to 4 carbon atoms. Examples include methylene (—CH₂—), propylidene (CH₃CH₂CH═), 1,2-ethandiyl (—CH₂CH₂—), etc.

As used herein, the term “phenylene” refers to a phenyl group with an additional hydrogen atom removed, i.e. a moiety with the structure of:

As used herein, the terms “carbocycle”, “carbocyclic” or “carbocyclyl” refer to a substituted or unsubstituted, stable monocyclic or bicyclic hydrocarbon ring system which is saturated, partially saturated or unsaturated, and contains from 3 to 10 ring carbon atoms. Accordingly the carbocyclic group may be aromatic or non-aromatic, and includes the cycloalkyl and aryl compounds defined herein. The bonds connecting the endocyclic carbon atoms of a carbocyclic group may be single, double, triple, or part of a fused aromatic moiety.

As used herein, the term “cycloalkyl” refers to a saturated or partially saturated mono- or bicyclic alkyl ring system containing 3 to 10 carbon atoms. A designation such as “C₅-C₇ cycloalkyl” refers to a cycloalkyl radical containing from 5 to 7 ring carbon atoms. Preferred cycloalkyl groups include those containing 5 or 6 ring carbon atoms. Examples of cycloalkyl groups include such groups as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexl, cycloheptyl, cyclooctyl, pinenyl, and adamantanyl.

As used herein, the term “aryl” refers to a substituted or unsubstituted, mono- or bicyclic hydrocarbon aromatic ring system having 6 to 12 ring carbon atoms. Examples include phenyl and naphthyl. Preferred aryl groups include unsubstituted or substituted phenyl and naphthyl groups. Included within the definition of “aryl” are fused ring systems, including, for example, ring systems in which an aromatic ring is fused to a cycloalkyl ring. Examples of such fused ring systems include, for example, indane, indene, and tetrahydronaphthalene.

As used herein, the terms “heterocycle”, “heterocyclic” or “heterocyclyl” refer to a substituted or unsubstituted carbocyclic group in which the ring portion includes at least one heteroatom such as O, N, or S. The nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen may be optionally substituted in non-aromatic rings. Heterocycles are intended to include heteroaryl and heterocycloalkyl groups.

As used herein, the term “heterocycloalkyl” refers to a cycloalkyl group in which one or more ring carbon atoms are replaced by at least one hetero atom such as —O—, —N—, or —S—. Examples of heterocycloalkyl groups include pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pirazolidinyl, pirazolinyl, pyrazalinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, dithiolyl, oxathiolyl, dioxazolyl, oxathiazolyl, pyranyl, oxazinyl, oxathiazinyl, and oxadiazinyl.

As used herein, the term “heteroaryl” refers to an aromatic group containing 5 to 10 ring carbon atoms in which one or more ring carbon atoms are replaced by at least one hetero atom such as —O—, —N—, or —S—. Examples of heteroaryl groups include pyrrolyl, furanyl, thienyl, pirazolyl, imidazolyl, thiazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxathiolyl, oxadiazolyl, triazolyl, oxatriazolyl, furazanyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, indolyl, isoindolyl, indazolyl, benzofuranyl, isobenzofuranyl, purinyl, quinazolinyl, quinolyl, isoquinolyl, benzoimidazolyl, benzothiazolyl, benzothiophenyl, thianaphthenyl, benzoxazolyl, benzisoxazolyl, cinnolinyl, phthalazinyl, naphthyridinyl, and quinoxalinyl. Included within the definition of “heteroaryl” are fused ring systems, including, for example, ring systems in which an aromatic ring is fused to a heterocycloalkyl ring. Examples of such fused ring systems include, for example, phthalamide, phthalic anhydride, indoline, isoindoline, tetrahydroisoquinoline, chroman, isochroman, chromene, and isochromene.

As used herein, the term “arylalkyl” refers to an alkyl group that is substituted with an aryl group. Examples of arylalkyl groups include, but are not limited to, benzyl, bromobenzyl, phenethyl, benzhydryl, diphenylmethyl, triphenylmethyl, diphenylethyl, naphthylmethyl, etc.

As used herein, the term “amino acid” refers to a group containing both an amino group and a carboxyl group. Embodiments of amino acids include α-amino, β-amino, γ-amino acids. The α-amino acids have a general formula HOOC—CH(side chain)-NH₂. In certain embodiments, substituent groups for the compounds of the present invention include the residue of an amino acid after removal of the hydroxyl moiety of the carboxyl group thereof; i.e., groups of formula —C(═O)CH(NH₂)-(side chain). The amino acids can be in their D, L or racemic configurations. Amino acids include naturally-occurring and non-naturally occurring moieties. The naturally-occurring amino acids include the standard 20 α-amino acids found in proteins, such as glycine, serine, tyrosine, proline, histidine, glutamine, etc. Naturally-occurring amino acids can also include non-α-amino acids (such as β-alanine, γ-aminobutyric acid, homocysteine, etc.), rare amino acids (such as 4-hydroxyproline, 5-hydroxylysine, 3-methylhistidine, etc.) and non-protein amino acids (such as citrulline, ornithine, canavanine, etc.). Non-naturally occurring amino acids are well-known in the art, and include analogs of natural amino acids. See Lehninger, A. L. Biochemistry, 2^(nd) ed.; Worth Publishers New York, 1975; 71-77, the disclosure of which is incorporated herein by reference. Non-naturally occurring amino acids also include α-amino acids wherein the side chains are replaced with synthetic derivatives. Representative side chains of naturally occurring and non-naturally occurring α-amino acids are shown below in Table 2.

TABLE 2 H CH₃ CH(CH₃)₂ CH₂CH(CH₃)₂ CH(CH₃)CH₂CH₃ CH₂OH CH₂SH CH(OH)CH₃ CH₂CH₂SCH₃ CH₂C₆H₅ (CH₂)₄NH₂ (CH₂)₃NHC(═NH)NH₂ CH₂COOH CH₂CH₂COOH CH₂CONH₂ CH₂CH₂CONH₂ CH₂CH₃ CH₂CH₂CH₃ CH₂CH₂CH₂CH₃ CH₂CH₂SH CH₂CH₂OH CH₂CH₂SCH₃ (CH₂)₃NH₂ (CH₂)₂CH(OH)CH₂NH₂ (CH₂)₃NHC(═O)NH₂ (CH₂)₂ONHC(═NH)NH₂ CH₂C(═O)NHCH₂COOH

As used herein, the term “subject” refers to a warm blooded animal such as a mammal, preferably a human, or a human child, which is afflicted with, or has the potential to be afflicted with one or more diseases and conditions described herein.

As used herein, a “therapeutically effective amount” refers to an amount of a compound of the present invention effective to prevent or treat the symptoms of particular disorder. Such disorders include, but are not limited to, those pathological and neurological disorders associated with the aberrant activity of the receptors described herein, wherein the treatment or prevention comprises inhibiting, inducing, or enhancing the activity thereof by contacting the receptor with a compound of the present invention.

As used herein, the term “pharmaceutically acceptable” refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem complications commensurate with a reasonable benefit/risk ratio.

As used herein, the term “unit dose” refers to a single dose which is capable of being administered to a patient, and which can be readily handled and packaged, remaining as a physically and chemically stable unit dose comprising either the active compound itself, or as a pharmaceutically acceptable composition, as described hereinafter.

All other terms used in the description of the present invention have their meanings as is well known in the art.

In another aspect, the present invention is directed to pharmaceutically acceptable salts of the compounds described above. As used herein, “pharmaceutically acceptable salts” includes salts of compounds of the present invention derived from the combination of such compounds with non-toxic acid or base addition salts.

Acid addition salts include inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric, nitric and phosphoric acid, as well as organic acids such as acetic, citric, propionic, tartaric, glutamic, salicylic, oxalic, methanesulfonic, para-toluenesulfonic, succinic, and benzoic acid, and related inorganic and organic acids.

Base addition salts include those derived from inorganic bases such as ammonium and alkali and alkaline earth metal hydroxides, carbonates, bicarbonates, and the like, as well as salts derived from basic organic amines such as aliphatic and aromatic amines, aliphatic diamines, hydroxy alkamines, and the like. Such bases useful in preparing the salts of this invention thus include ammonium hydroxide, potassium carbonate, sodium bicarbonate, calcium hydroxide, methylamine, diethylamine, ethylenediamine, cyclohexylamine, ethanolamine and the like.

In addition to pharmaceutically-acceptable salts, other salts are included in the invention. They may serve as intermediates in the purification of the compounds, in the preparation of other salts, or in the identification and characterization of the compounds or intermediates.

The pharmaceutically acceptable salts of compounds of the present invention can also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, ethyl acetate and the like. Mixtures of such solvates can also be prepared. The source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent. Such solvates are within the scope of the present invention.

The present invention also encompasses the pharmaceutically acceptable prodrugs of the compounds disclosed herein. As used herein, “prodrug” is intended to include any compounds which are converted by metabolic processes within the body of a subject to an active agent that has a formula within the scope of the present invention. Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.) the compounds of the present invention may be delivered in prodrug form. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Prodrugs, Sloane, K. B., Ed.; Marcel Dekker: New York, 1992, incorporated by reference herein in its entirety.

It is recognized that compounds of the present invention may exist in various stereoisomeric forms. As such, the compounds of the present invention include both diastereomers and enantiomers. The compounds are normally prepared as racemates and can conveniently be used as such, but individual enantiomers can be isolated or synthesized by conventional techniques if so desired. Such racemates and individual enantiomers and mixtures thereof form part of the present invention.

It is well known in the art how to prepare and isolate such optically active forms. Specific stereoisomers can be prepared by stereospecific synthesis using enantiomerically pure or enantiomerically enriched starting materials. The specific stereoisomers of either starting materials or products can be resolved and recovered by techniques known in the art, such as resolution of racemic forms, normal, reverse-phase, and chiral chromatography, recrystallization, enzymatic resolution, or fractional recrystallization of addition salts formed by reagents used for that purpose. Useful methods of resolving and recovering specific stereoisomers described in Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds; Wiley: New York, 1994, and Jacques, J., et al. Enantiomers, Racemates, and Resolutions; Wiley: New York, 1981, each incorporated by reference herein in their entireties.

It is further recognized that functional groups present on the compounds of Formula I may contain protecting groups. For example, the amino acid side chain substituents of the compounds of Formula I can be substituted with protecting groups such as benzyloxycarbonyl or t-butoxycarbonyl groups. Protecting groups are known per se as chemical functional groups that can be selectively appended to and removed from functionalities, such as hydroxyl groups and carboxyl groups. These groups are present in a chemical compound to render such functionality inert to chemical reaction conditions to which the compound is exposed. Any of a variety of protecting groups may be employed with the present invention. Preferred protecting groups include the benzyloxycarbonyl (Cbz; Z) group and the tert-butyloxycarbonyl (Boc) group. Other preferred protecting groups according to the invention may be found in Greene, T. W. and Wuts, P. G. M., “Protective Groups in Organic Synthesis” 2d. Ed., Wiley & Sons, 1991.

Synthesis

The compounds of the present invention may be prepared in a number of methods well known to those skilled in the art, including, but not limited to those described below, or through modifications of these methods by applying standard techniques known to those skilled in the art of organic synthesis. All processes disclosed in association with the present invention are contemplated to be practiced on any scale, including milligram, gram, multigram, kilogram, multikilogram or commercial industrial scale.

It will be appreciated that the compounds of the present invention may contain one or more asymmetrically substituted carbon atoms, and may be isolated in optically active or racemic forms. Thus, all chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. It is well known in the art how to prepare such optically active forms. For example, mixtures of stereoisomers may be separated by standard techniques including, but not limited to, resolution of racemic forms, normal, reverse-phase, and chiral chromatography, preferential salt formation, recrystallization, and the like, or by chiral synthesis either from active starting materials or by deliberate chiral synthesis of target centers.

As will be readily understood, functional groups present on the compounds of Formula I may contain protecting groups. For example, the amino acid side chain substituents of the compounds of Formula I can be substituted with protecting groups such as benzyloxycarbonyl or t-butoxycarbonyl groups. Protecting groups are known per se as chemical functional groups that can be selectively appended to and removed from functionalities, such as hydroxyl groups and carboxyl groups. These groups are present in a chemical compound to render such functionality inert to chemical reaction conditions to which the compound is exposed. Any of a variety of protecting groups may be employed with the present invention. Preferred protecting groups include the benzyloxycarbonyl (Cbz; Z) group and the tert-butyloxycarbonyl (Boc) group. Other preferred protecting groups according to the invention may be found in Greene, T. W. and Wuts, P. G. M., Protective Groups in Organic Synthesis, 2d. Ed., Wiley & Sons, 1991.

The general routes to prepare the examples shown in Table 1 of the present invention are shown in the Scheme A, Scheme B, Scheme C and Scheme D. The reagents and starting materials are commercially available, or readily synthesized by well-known techniques by one of ordinary skill in the arts. All substituents in the synthetic Schemes, unless otherwise indicated, are as previously defined.

Compounds of general structure (A) and/or (I) were prepared according to Scheme A.

Step 1: Synthesis of Compounds of General Structure C:

An appropriate aromatic or heteroaromatic alcohol or thiol of general formula A is reacted with an appropriate halo-aryl or halo-heteroaryl aldehyde or acid of general formula B, in a polar aprotic solvent as DMF and like at reflux temperature to give the corresponding aldehyde or acid compound C wherein Ar, X, R² and R³ are as defined in the final product and W represents the acid or the aldehyde group. An appropriate aromatic or heteroaromatic alcohol or thiol of general formula A is one where Ar is as defined in the final product and X represents oxygen or sulfure atoms. An appropriate halo-aryl or halo-heteroaryl aromatic aldehyde or acid of general formula B is one where R² and R³ are as defined in the final product, W is an acid or an aldehyde group and hal is an halogen atom: F, Cl, Br. Upon completion, the reaction mixture is quenched by an appropriate quenching agent and the product, compound C, is isolated by conventional methods commonly employed by those skilled in the art. Compounds of general formula C may also be commercially available.

Step 2: Synthesis of Compounds of General Structure D:

The appropriate compound C of the preceding step, dissolved in a protic polar solvent as isopropanol and like, may be treated with a suitable reducing agent such as metallic hydrides. For example, the compound C may be treated with sodium borohydride (or other standard reductive conditions as LiAlH4, diisobutylaluminium hydride and like) in order to provide the corresponding alcohol of general formula D. When the starting material is a compound C bearing an acidic function (W is COOH), the reduction reaction might be performed after activation of the carboxy moiety with an activating agent as isobutylchloroformate and like, or by conventional methods commonly employed by those skilled in the art.

Step 3: Synthesis of Compounds of General Structure E:

In step 3, the alcohol moiety of compound D is converted to the corresponding thiouronium salt.

In a particular embodiment, the compound E is formed by reacting the compound D with a suitable acid. In certain aspects, the suitable acid is selected from the group consisting of hydrobromic acid, hydrochloric acid or sulfuric acid.

For example, an appropriate amount of thiourea in 48% HBr and water is warmed (preferably to 60-70° C.), followed by addition of compound D. The reaction mixture is refluxed and the stirring is continued for an additional period of time for completion of the reaction. The reaction mixture is cooled to room temperature (in some cases, an ice-bath might be needed) and the precipitated solid is optionally filtered and thoroughly washed with water to generate compound E. Sometimes there is an oil in place of the solid: in that case, the oil is thoroughly washed with water by decantation and used directly in step 4.

Step 4: Synthesis of Compounds of General Structure I Wherein q=0

The thiouronium salt of general structure E is first converted into the corresponding thiol which further undergoes a substitution reaction with an appropriate reactant of generic structure LG-Y—R¹ wherein Y is as defined in the final product and LG is a suitable leaving group (for example an halogen atom as Cl, Br) to generate compound I wherein q is 0.

In step 4, the wet solid (or the oil with some remaining water) from the previous step is taken into additional water and treated with an aqueous base, preferably sodium hydroxide solution. The mixture is warmed preferably to 70-80° C., but in some cases a higher temperature might be needed and to it an appropriate amount of LG-Y—R¹ in water (or in some cases, an alcoholic solvent) is added. The reaction mixture is refluxed for an appropriate period of time, cooled, taken into water and sometimes washed with an organic solvent (preferably ether). The basic aqueous layer is acidified with an inorganic acid solution (e.g. aqueous HCl solution). The aqueous (acidic) solution is then extracted several times into an organic solvent (e.g. ether or ethyl acetate). The combined organic layer is washed with brine, dried (MgSO₄ or Na₂SO₄) and concentrated to give the crude product that may be used directly in the next step. However, purification could be achieved by employing known purification techniques (e.g. recrystallization or column chromatography) to provide pure compound I wherein q is 0, Ar, X, R¹, Y¹, R² and R³ are as defined in the final product.

In addition, at Step 4, when the obtained compound I is an acid (R¹ is COOH), appropriately, it may be converted into the corresponding alkyl ester by conventional methods commonly employed by those skilled in the art.

Step 5: Synthesis of Compounds of General Structure I Wherein q is 1 or 2:

Compounds of structure I wherein q is 0 may optionally be oxidized to generate compounds of structure I wherein q is 1 or 2. Compound I wherein q is 1 is prepared under mild conditions by reacting compound I wherein q is 0 in an appropriate solvent with an appropriate oxidizing agent. An appropriate oxidizing agent is one that oxidizes the sulphide group of compound I (wherein q is 0). The corresponding product is isolated and purified by methods well known in the art.

For example, to solution of compound I (wherein q is 0) in acetic acid, an appropriate oxidizing agent (e.g. 30% wt H₂O₂, 1 equivalent) in the acetic acid is slowly added. Stirring is continued at low temperature until the disappearance of the starting material, as evidenced by various analytical techniques. The reaction mixture is concentrated. The desired product (compound I wherein q is 1) is purified, if needed, by employing known purification techniques (preferably by column chromatography and/or crystallization). In some cases, the oxidation is performed by employing 50% H₂O₂ in glacial acetic acid solvent.

Compound of formula I wherein q is 2, may be obtained from the appropriate compound of formula I wherein q is either 0 or 1 under more drastic reaction conditions such as H₂O₂ (more than 2 equivalents) in acidic medium, under heating, at temperature comprise between room temperature and the boiling temperature of the solvent, preferably between 40 and 60° C., for a time sufficient to obtain the desired product, approximately between 2 and 10 hours, preferably approximately 8 hours.

The following scheme (Scheme B) corresponds to the synthesis of compounds of general structure I wherein R¹ is C(═O)NR¹²R¹³.

The different steps 1, 2, 3 and 4 were as described in scheme A.

In addition, at Step 4, when the obtained compound I is an acid (R is H), appropriately, it may be converted into the corresponding alkyl ester by conventional methods commonly employed by those skilled in the art.

Then, two different synthetic routes may optionally be used to generate compounds I wherein R¹ is C(═O)NR¹²R¹³.

Route A

Step 5: Synthesis of Compounds of General Formula I Wherein q is 0:

In step 5, the appropriate carboxylic acid or ester of general formula I (wherein q is 0) is reacted with an appropriate amine of general structure NHR¹²R¹³ and converted into the corresponding amide of general formula I wherein q is 0 and Ar, X, R², R³, Y, R¹² and R¹³ are as defined in the final product.

Compound I (wherein q is 0 and R¹ is COOMe) may be reacted with Ammonium hydroxide (28% aqueous solution as example) or ammonia gas to give the desired compound I (wherein q is 0 and R¹² and R¹³ are H). Alternatively, compound I (wherein q is 0 and R1 is COOH) may be reacted with an appropriate amine of general formula NHR¹²R¹³, a coupling reagent such as EDCI or DCCI, or a polymer supported coupling reagent (N-cyclohexyl carbodiimide), and optionally HOBT in an aprotic solvent as methylene chloride and like to provide amide of general formula I wherein q is 0. An appropriate amine is one which correlates to R¹² and R¹³ as defined in the final product. In some cases, when the appropriate amide bears a protecting group as the tert-butyloxycarbonyl (“Boc”) and like on a second nitrogen group, N-boc amine is de-protected in a subsequent step. De-protection may be performed at room temperature by acid treatment such as 4N HCl in 1,4-dioxane or trifluoroacetic acid in CH₂Cl₂.

Step 6: Synthesis of Compounds of General Structure I Wherein q is 1 or 2:

Compounds of structure I wherein q is 0 may optionally be oxidized to generate compounds of structure I wherein q is 1 or 2 according to the procedure described previously in Scheme A (step 5).

Route B

Route B may alternatively be used to process appropriately compound I wherein R¹ is C(═O)NR¹²R¹³.

In step 5, the process consisted, in oxidizing an appropriate compound I wherein q is 0 to generate the corresponding sulfoxide or sulfone as described above in step 6, which, in turn, is reacted with an appropriate amine of general formula NHR¹²R¹³, in the next step, to give raise to the corresponding amide (compound I wherein q is 1 or 2) as described above in step 5.

Scheme C, corresponds to an alternative pathway to generate compounds of general structure I wherein X is different from O or S.

Step 1: Synthesis of Compounds of General Structure J:

An appropriate aromatic or heteroaromatic halide of general formula H substituted with a nitro group in a suitable position as defined in the final product is reacted with an appropriate thiol-substituted alkylcarboxylic acid or ester of structure HS—Y—R¹ (wherein R¹ is H or alkyl, and Y is defined as in the final compound) in an aprotic solvent such as acetone and like and in the presence of an inorganic base as potassium carbonate and a catalyst as potassium iodine and like to generate compound J. The reaction is performed at reflux temperature.

Step 2: Synthesis of Compounds of General Structure M:

Route A

i) Oxidation Reaction: Synthesis of Compound of General Formula L

Then, appropriate compounds of general formula J wherein R¹, R² and R³ and Y are as defined in the final product are prepared by reacting compound J in an appropriate solvent with an appropriate oxidizing agent. An appropriate oxidizing agent is one that oxidizes the sulfide group of compound J. The corresponding product is isolated and purified by methods well known in the art.

For example, to solution of compound J in acetic acid, an appropriate oxidizing agent (e.g. 30% bw H₂O₂, 1 equivalent) in the same solvent is slowly added. Stirring is continued until the disappearance of the starting material, as evidenced by various analytical techniques. The reaction mixture is concentrated. The desired product (compound L wherein q is 1) is purified, if needed, by employing known purification techniques (preferably by column chromatography and/or crystallization). In some cases, the oxidation is performed by employing 50% H₂O₂ in glacial acetic acid solvent.

Compound of formula L wherein q is 2, may be obtained under more drastic reaction conditions such as H₂O₂ (more than 2 equivalents) in acidic medium, under heating, preferably at temperature comprise between room temperature and the boiling temperature of the solvent, preferably between 40 and 60° C., for a time sufficient to obtain the desired product, usually approximately between 2 and 10 hours, preferably approximately 8 hours.

ii) Catalytic Hydrogenation

Appropriate amino compound of general formula M may be produced by catalytic hydrogenation from the appropriate nitro compound of formula L. The hydrogenation reaction is performed under pressure in a hydrogen atmosphere and catalytic conditions using a catalyst as palladium on carbon or platinium oxide and like in an alcoholic solvent such as methanol and like.

Route B

i) Synthesis of Compound of General Formula K

Before undergoing oxidation reaction, appropriately, compound J wherein R¹ is a carboxylic acid may be reacted with an appropriate amine of structure NHR¹²R¹³. The amidation reaction is performed using a coupling such as EDCI or DCCI, or a polymer supported coupling reagent (N-cyclohexyl carbodiimide) and optionally HOBT in an aprotic solvent as methylene chloride and like to give the desired amide of general formula K.

Alternatively, compound J wherein R¹ is a carboxylic acid may be converted into the corresponding alkyl ester by conventional methods commonly employed by those skilled in the art. Then, the ester is reacted with an appropriate amine of general structure NHR¹²R¹³ in the presence of trimethyl aluminium hydride for instance or with ammonium hydroxide (28% aqueous solution as example) or ammonia gas to give the desired compound K.

ii) Oxidation and Catalytic Hydrogenation of Compound K

Compounds K wherein R¹ is an amide are then oxidized according to the process described above for Route A to generate the corresponding compound of formula L which, in turn, is reduced in compound M according to the process described above in Route A.

Route C

The compound of general formula K wherein R¹ is the appropriate amide C(═O)NHR¹²R¹³, R² and R³ and Y are as defined in the final product prepared by amidation of compound J is reduced in compound M′ according to the process described above in route A. Then the corresponding compound M wherein q is 1 or 2 is generated as according to the oxidation process described in Route A.

Step 3: Synthesis of Compounds of General Structure I Wherein X is NH, C(R²²)₂NH, C(═O)NH, S(O)₂NH.

Compounds of general formula I, wherein Ar, X, q, R², R³, Y and R¹ are as defined in the final product may be prepared in a one step procedure in suitable experimental conditions as to obtain the target X definition.

For example, compound of formula I wherein X is NH may be obtained by coupling an appropriate amine M with an appropriate boronic acid in an aprotic solvent as dichloromethane and the like. The reaction is carried out in the presence of a base such as 2,6-lutidine and like as pyridine, triethylamine, diisopropylethylamine and in catalytic conditions using copper(II) acetate. An appropriate boronic acid is one which correlates to Ar as defined in the final product.

Compounds of general formula I, wherein X is C(R²²)₂NH may be prepared in a one step procedure by alkylation an appropriate amine M with a suitable alkylating agent in an aprotic solvent as DMF, dichloromethane and the like. A suitable alkylating agent is one which correlates to Ar and R²² as defined in the final product.

Compounds of formula I wherein X is an amide may be obtained by aroylation of an appropriate amine M with an appropriate aromatic or heteroaromatic halide in an aprotic solvent as dichloromethane and the like. The reaction is carried out in the presence of a base such as pyridine, and the like triethylamine, diisopropylethylamine. An appropriate aromatic or heteroaromatic halide is one which correlates to Ar as defined in the final product.

Compounds of general formula I, wherein X is S(O)₂NH may be prepared in a one step procedure by sulfonation of an appropriate amine M with an appropriate aromatic or heteroaromatic sulfonyl chloride in an aprotic solvent. The reaction is carried out in the presence of a base such as pyridine, and like triethylamine, diisopropylethylamine. An appropriate aromatic or heteroaromatic sulfonyl chloride is one which correlates to Ar as defined in the final product.

Compounds of general structure I were also generated according to Scheme D.

Scheme D, Synthesis of Compounds of General Structure I

Step 1: Synthesis of Compounds of General Structure O

An appropriate xylene of general formula N bearing two leaving groups in a suitable position as defined in the final product is reacted with appropriate thiol of structure HS—Y—R¹ wherein Y and R1 are as defined in the final product to generate compound of general formula O. The reaction is carried out in an aprotic solvent such as DMF and like and in the presence of an inorganic base as potassium carbonate and at room temperature in an argon atmosphere.

Step 2: Synthesis of Compounds of General Structure I Wherein q is 0:

Then compound O is reacted with an appropriate aryl or heteroaryl alcohol, amine or thiol to generate compound of general formula I wherein q is 1 and Ar, X, R¹, R² and R³ are as defined in the final product.

In addition, when R¹ is an ester function, compound I may be hydrolysed at solvent reflux temperature and in the presence of an inorganic base before the amidification step.

Step one and step 2 may be processed without isolation of the intermediate 0 (one pot procedure).

Step 3: Synthesis of Compounds of General Structure I Wherein q is 1 or 2

i) Oxidation Reaction

Then, appropriate compounds of general formula I wherein R¹, R², R³, X, q and Y are as defined in the final product are prepared by reacting compound I in an appropriate solvent with an appropriate oxidizing agent. An appropriate oxidizing agent is one that oxidizes the sulfide group of compound I. The corresponding product is isolated and purified by methods well known in the art.

For example, to solution of compound I in acetic acid, an appropriate oxidizing agent (e.g. 30% wt H₂O₂, 1 equivalent) in the same solvent is slowly added. Stirring is continued until the disappearance of the starting material, as evidenced by various analytical techniques. The reaction mixture is concentrated. The desired product (compound I wherein q is 1) is purified, if needed, by employing known purification techniques (preferably by column chromatography and/or crystallization). In some cases, the oxidation is performed by employing 50% H₂O₂ in glacial acetic acid solvent.

Compound of formula I wherein q is 2, may be obtained under more drastic reaction conditions such as H₂O₂ (more than 2 equivalents) in acidic medium, under heating, preferably at temperature comprise between room temperature and the boiling temperature of the solvent, preferably between 40 and 60° C., for a time sufficient to obtain the desired product, usually approximately between 2 and 10 hours, preferably approximately 8 hours.

ii) Synthesis of Compound of General Formula I Wherein R¹ is C(═O)NHR¹²R¹³

Before undergoing oxidation reaction, appropriately, compound I wherein q is 0 and R¹ is an ester or an acid function may be reacted with an appropriate amine of structure NHR¹²R¹³. as already described in schema B, route A.

Compounds I wherein R¹ is an amide are then oxidized according to the processes described above to generate the corresponding compound of formula I wherein q is 1 or 2.

EXAMPLES

Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments. These examples are given for illustration of the invention and are not intended to be limiting thereof.

I—Compounds Prepared According to Schemes A and B.

The following Examples 1 to 112 were synthesized according to Schemes A and B.

A—Preparation of Compounds C

Compound 1

Compound C wherein Ar is 3,4-DiClPhenyl, X is O, substitution in para position, W is C(═O)H.

To a stirred solution of A (aldehyde wherein Ar is 3,4-DiClPhenyl, X is O, 39 g, 239 mmol) in DMF (200 mL), parafluorobenzaldehyde (compound B; 26 mL; 242 mmol) and cesium carbonate (80 g; 250 mmol) were added. The mixture was refluxed for 3 hours and then cooled to room temperature. After dilution with brine (800 mL), the resulting precipitate was extracted with Et₂O (4×250 mL). The organic layer was washed with brine (3×300 mL), water (2×300 mL), and then dried over MgSO₄ and concentrated in vacuo. Trituration of the resulting residue with cold Et₂O, filtration and drying under vacuum gave 42 g (157 mmol) of compound 1 as an off-white solid.

Yield=66%.

R_(f)=0.94 (95:5 methylenechloride/methanol).

According to the procedure as described for compound 1, the following compounds were prepared.

Compound 2

Compound C wherein Ar is 3,4-DiClPhenyl, X is O, substitution in ortho position, W is C(═O)H.

Reagents: compound A (wherein Ar is 3,4-DiClPhenyl, X is O, 39 g, 239 mmol) and orthofluorobenzaldehyde (compound B; 26 mL; 242 mmol).

Yield=35% (22.3 g; 83 mmol of compound 2).

R_(f)=0.73 (eluent: 8:2 cyclohexane/ethylacetate).

Compound 3

Compound C wherein Ar is 4-ClPhenyl, X is S, substitution in para position, W is C(═O)H.

Reagents: compound A (wherein Ar is 4-ClPhenyl, X is S, 26.3 g, 182 mmol) and parafluorobenzaldehyde (compound B; 20 mL; 242 mmol).

Yield=88% (40 g; 160 mmol of compound 3 as a yellow powder).

R_(f)=0.57 (eluent: 8:2 cyclohexane/ethylacetate).

Compound 4

Compound C wherein Ar is 4-ClPhenyl, R² is 3-Cl, X is O, substitution in para position, W is C(═O)H.

To a stirred solution of A (wherein Ar is 4-ClPhenyl, X is O, 23.4 g, 182 mmol) in DMF (150 mL), 2-chloro-4-fluorobenzaldehyde (compound B; 28.8 g; 182 mmol) and cesium carbonate (61 g; 187 mmol) were added. The mixture was refluxed for 4 hours and then cooled to room temperature. After dilution with brine (800 mL), the resulting precipitate was extracted with Et₂O (4×250 mL). The organic layer was washed with brine (3×300 mL), water (2×300 mL), and then dried over MgSO₄ and concentrated in vacuo. The crude product was purified by flash chromatography (eluent: cyclohexane/ethylacetate 9/1) to afford compound 4 (20.5 g; 77 mmol)

Yield=42%.

R_(f)=0.75 (9:1 cyclohexane/ethylacetate).

Compound 4a

Compound C wherein Ar is 4-ClPhenyl, X is O, R² is 4′-Cl, R³ is H, substitution in ortho position, W is C(═O)H.

To a stirred solution of 4-chlorophenol (compound A wherein Ar is 4-ClPhenyl, X is O, 20.3 g, 155 mmol) in DMF (150 mL), 4-chloro-2-fluorobenzaldehyde (compound B; 25 g; 158 mmol) and potassium carbonate (30 g; 217 mmol) were added. The mixture was stirred for 15 hours. After dilution with brine (300 mL), the resulting precipitate was extracted with Et₂O (4×250 mL). The organic layer was washed with brine (3×300 mL), water (2×300 mL), and then dried over MgSO₄ and concentrated in vacuo to give compound 4a as an oil.

Yield=100% (41.4 g; 155 mmol)

R_(f)=0.61 (8:2 cyclohexane/ethylacetate).

B—Preparation of compounds D

Compound 5

Compound D wherein Ar is 3,4-DiClPhenyl, X is O, substitution in ortho position.

To a stirred solution of compound 2 (22.3 g, 83 mmol) in isopropanol (120 mL), sodium borohydride (3.16 g; 83 mmol) was added. The mixture was stirred at room temperature for one hour, before adding water (350 mL). After stirring for additional 3 hours, the aqueous layer was extracted with Et₂O (2×300 mL). The combined organic layer was washed with water (3×300 mL), dried over MgSO₄ and concentrated in vacuo to give compound 5 as an orange oil.

Yield=95% (21.3 g; 79 mmol).

R_(f)=0.35 (eluent: methylenechloride).

The following compound were prepared according to the procedure described for compound 5:

Compound 6

Compound D wherein Ar is 3,4-DiClPhenyl, X is O, substitution in para position.

Reagents: compound 1 (38 g; 142 mmol) and sodium borohydride (5.37 g; 142 mmol).

Yield=43% (16.6 g; 62 mmol).

R_(f)=0.56 (eluent: 95:5 methylenechloride/methanol).

Compound 7

Compound D wherein Ar is 4-ClPhenyl, X is S, substitution in para position;.

Reagents: compound 3 (40 g; 161 mmol) and sodium borohydride (6.09 g; 161 mmol). Compound 7 was generated as a yellow powder.

Yield=99% (40 g; 160 mmol).

R_(f)=0.21 (eluent: methylenechloride).

Compound 8

Compound D wherein Ar is Phenyl, X is O, substitution in ortho position.

To an ice cold solution of compound C (wherein Ar is Phenyl, X is O, substitution in ortho position, W is C(═O)OH; 25 g; 117 mmol) and N-methylmorpholine (20 ml; 180 mmol) in THF (100 mL) under N₂, isobutylchloroformate (17 ml; 131 mmol) was added. After stirring for 15 minutes, sodium borohydride (12.5 g; 330 mmol) was added, followed by 50 mL of water. The ice bath was removed and stirring was continued overnight. After cooling, the mixture was made acidic with hydrochloric acid and extracted with Et₂O (2×200 mL). The combined organic layer was washed with water (2×200 mL), dried (MgSO₄) and evaporated to dryness. The crude product was purified by flash column chromatography (eluent: ethyl acetate/cyclohexane (1/9) to produce compound 8 as an colorless oil.

Yield=70% (16.4 g; 82 mmol).

R_(f)=0.50 (eluent: 7:3 cyclohexane/ethylacetate).

The following compound was prepared according to the procedure as described for compound 8:

Compound 9

Compound D wherein Ar is Phenyl, X is O, substitution in para position.

Reagents: compound C (wherein Ar is Phenyl, X is O, substitution in para position, W is C(═O)OH; 38 g; 142 mmol), isobutylchloroformate (13.6 mL; 105 mmol) and sodium borohydride (10 g; 264 mmol).

Yield=46% (8.6 g; 43 mmol).

R_(f)=0.58 (eluent: 1:1 ethylacetate/cyclohexane).

Compound 10

Compound D (wherein Ar is 4-ClPhenyl, R² is 3-Cl, X is O, substitution in para position)

To a stirred solution of compound 4 (20.5 g, 77 mmol) in isopropanol (100 mL), sodium borohydride (2.9 g; 77 mmol) was added. The mixture was stirred at room temperature for one night, before adding water (350 mL). After stirring for additional 3 hours, the solvent was removed by decantation. The resulting residue was taken into a mixture of water (400 mL) and ether (400 mL). The organic layer was washed with water (2×150 mL), dried over MgSO₄ and concentrated in vacuo to furnish an oil that was purified by column chromatography (eluent methylenechloride) to afford compound 10 as a yellow oil after solvent evaporation.

Yield=30% (6.3 g; 23 mmol).

R_(f)=0.45 (eluent: methylenechloride).

Compound 10a

Compound D wherein Ar is 4-ClPhenyl, X is O, R² is 4′-Cl, R³ is H, substitution in ortho position

To a stirred solution of compound 4a (41.4 g, 155 mmol) in isopropanol (250 mL), sodium borohydride (6.8 g; 180 mmol) was added. The mixture was stirred at room temperature for one night, before adding water (1.5 L). After stirring for additional 3 hours, the resulting precipitated solid was filtered off, washed with water and dried in vacuo to generate compound 10a as a white powder.

Yield=63% (26.2 g; 97 mmol).

R_(f)=0.61 (eluent: 98:2 methylenechloride/methanol).

C—Preparation of Compounds E

Compound 11

Compound E wherein Ar is 4-ClPhenyl, X is O, substitution in para position.

To a stirred mixture of thiourea (6 g; 79 mmol), 48% HBr (34 mL) and water (6 mL) at 60° C., compound D (Ar is 4-ClPhenyl, X is O, substitution in para position; 14.6 g; 62 mmol) prepared according to scheme A, step 1 and 2, was added portionwise. The reaction mixture was refluxed for one hour, cooled and filtered. The resulting residue was washed with water (3×30 mL) and dried under vacuum to generate 21 g of compound 11 as the major product. It was used in the next step without any further purification.

D—Preparation of Compounds I—Scheme A

Example 1

Compound I wherein Ar is 3,4-DiClPhenyl, X is O, q is 0, substitution in para position, Y—R¹ is CH₂COOH.

To a stirred mixture of thiourea (6 g; 79 mmol), 48% HBr (34 mL) and water (6 mL) at 60° C., compound 6 (16.6 g; 62 mmol) was added fractionwise. The reaction mixture was refluxed for one hour, and then cooled to room temperature and filtered. The resulting residue was washed with water (3×30 mL) and then poured into aqueous NaOH (32%, 30 mL). The resulting aqueous mixture was stirred and heated to 70° C. before adding dropwise a solution of chloracetic acid (6.8 g, 72 mmol) in aqueous sodium hydrogenocarbonate (16 mL). The mixture was then refluxed for one hour, cooled to room temperature, diluted with water (150 mL), acidified to pH 2 with 4N aqueous HCl and then extracted into Et₂O (250 mL). The dried (MgSO4) organic phase was evaporated to dryness to give a residue. The crude product was purified by flash chromatography (eluent: methylenechloride/methanol (9/1) to afford Example 1 (13.2 g; 38.5 mmol) as an orange oil.

Yield=62%.

R_(f)=0.47 (eluent: 9:1 methylenechloride/methanol).

According to the process as described above, the following compounds were prepared:

Example 2

Compound I wherein Ar is 3,4-DiClPhenyl, X is O, q is 0, substitution in ortho position; Y—R¹ is CH₂COOH.

Reagents: compound 5 (21.3 g; 79 mmol) following the same procedure and chloracetic acid (6.8 g, 72 mmol).

Yield=49% (16.8 g; 49 mmol).

R_(f)=0.53 (eluent: 9:1 methylenechloride/methanol).

Example 3

Compound I wherein Ar is 4-ClPhenyl, X is S, q is 0, substitution in para position, Y—R¹ is CH₂COOH.

Reagents: compound 7 (15.6 g, 62 mmol) and chloracetic acid (4.16 g, 44 mmol).

Yield=82% (16.5 g; 51 mmol of compound 12 obtained as an off-white solid)

R_(f)=0.44 (eluent: 90:10 methylenechloride/methanol).

Example 4

Compound I wherein Ar is Phenyl, X is O, q is 0, substitution in para position, Y—R¹═CH₂ COOH.

Reagents: compound 9 (8 g, 40 mmol) and chloracetic acid (4.16 g, 44 mmol).

Yield=90% (9.9 g; 36 mmol).

R_(f)=0.42 (eluent: 90:10 methylenechloride/methanol).

Example 5

Compound I wherein Ar is Phenyl, X is O, q is 0, substitution in ortho position, Y—R¹ is CH₂ COOH.

Reagents: compound 8 (8 g, 40 mmol) and chloracetic acid (4.16 g, 44 mmol).

Yield=64% (8.4 g; 31 mmol).

R_(f)=0.49 (eluent: 90:10 methylenechloride/methanol).

Example 6

Compound I wherein Ar is 4-ClPhenyl, R² is 3-Cl, X is O, q is 0, substitution in para position, Y—R¹═CH₂COOH.

To a stirred mixture of thiourea (2.2 g; 29 mmol), 48% HBr (12 mL) and water (2 mL) at 60° C., compound 10 (6.3 g; 23.4 mmol) was added fractionwise. The reaction mixture was refluxed for fifteen minutes, and then cooled to room temperature and filtered. The resulting residue was washed with water (3×30 mL) and then poured into aqueous NaOH (32%, 12 mL). The resulting aqueous mixture was stirred and heated to 70° C. before adding dropwise a solution of sodium chloracetate (3 g, 26 mmol). The mixture was then refluxed for one hour, cooled to room temperature, diluted with water (150 mL), acidified to pH 2 with 4N aqueous HCl and then extracted into Et₂O (250 mL). The dried (MgSO4) organic phase was evaporated to dryness to afford Example 6 (13.2 g; 38.5 mmol) as an yellow oil after solvent evaporation.

Yield=69% (6.9 g; 20 mmol)

R_(f)=0.36 (eluent: 93:7 methylenechloride/methanol).

Example 7

Compound I wherein Ar is 4-ClPhenyl, X is O, q is 0, substitution in para position, Y—R¹ is CH₃.

To a stirred mixture of compound 11 (7.3 g; 19.5 mmol) in 0.6N aqueous sodium hydroxyde (20 mL), dimethylsulfate (2 mL, 18 mmol) was added. The reaction mixture was then refluxed for two hours, cooled and acidified with 1N aqueous hydrochloride. The precipitate was extracted with a mixture of ether (50 mL) and ethylacetate (50 mL). The organic layer was washed with water (2×100 mL) and concentrated under vacuum. The resulting residue was purified by column chromatography (eluent: methylene chloride) to produce 2.2 g of Example 7 as the major product (oil). It was used in the next step without any further purification.

Example 8 1-Methane sulfinylmethyl-4-(4-chlorophenoxy)-benzene

Compound I wherein Ar is 4-ClPhenyl, X is O, q is 1, substitution in para position, Y—R¹ is CH₃.

To a solution of Example 7 (2.2 g; 8.3 mmol) in acetic acid (30 mL), a 30% by wt hydrogen peroxide solution (0.99 mL; 9.7 mmol) was added. The mixture was stirred until no more starting material was detected (HPLC), concentrated under high vacuum. The resulting residue was purified by column chromatography (eluent: methylene chloride/methanol 95/5) to produce an oil which is taken up into methylene chloride (100 mL). The organic phase was washed with an aqueous solution of sodium hydroxide (2×50 mL), water (1×50 mL), dried (MgSO₄) and concentrated in vacuo to produce Example 8 as a white powder.

Yield=39% (0.9 g; 3.2 mmol)

¹H-NMR (DMSO-d₆) δ: 7.45 (d, 2H), 7.3 (d, 2H), 7.0 (m, 4H), 4.2 (d, 1H), 3.9 (d, 1H), 2.45 (s, 3H).

MS: 303 (M+Na).

Example 9 Di [4-(4-Chloro-phenoxy)-phenylmethyl]sulfoxyde

Compound I wherein Ar is 4-ClPhenyl, X is O, q is 1, substitution in para position, Y—R¹ is CH₂[4(4-ClPhenoxy)phenyl]

0.6 g of Example 9 was obtained as a by product during the preparation process of example 8 as white powder.

¹H-NMR (DMSO-d₆) δ: 7.45 (d, 2H), 7.3 (d, 2H), 7.0 (m, 4H), 4.2 (d, 1H), 3.8 (d, 1H).

MS: 483 (M+H).

Example 10 1-Methanesulfinylmethyl-4-(3,4-dichlorophenoxy)-benzene

Compound I wherein Ar is 3,4-DiClPhenyl, X is O, q is 1, substitution in para position, Y—R¹ is CH₃ was prepared following the same multistep general method as described in scheme A for Example 8 utilizing the appropriate substituted aryl alcohol.

MS: 337 (M+Na).

Example 10a

Compound I wherein Ar is 4-ClPhenyl, X is O, R² is 4′-Cl, R³ is H, q is 0, substitution in ortho position, Y—R¹ is CH₂COOH

To a stirred mixture of thiourea (6 g; 79 mmol), 48% HBr (34 mL) and water (6 mL) at 60° C., compound 10a (17.4 g; 65 mmol) was added portionwise. The reaction mixture was refluxed for one hour, cooled and filtered. The resulting residue was washed with water (3×30 mL) and then poured into aqueous NaOH (32%, 30 mL). The resulting aqueous mixture was stirred and heated to 70° C. before adding dropwise a solution of sodium chloracetate (8.4 g, 72 mmol) in water (16 mL). The mixture was then refluxed for one hour, cooled to room temperature, diluted with water (150 mL), acidified to pH 2 with 4N aqueous HCl and then extracted into Et₂O (250 mL). The dried (MgSO4) organic phase was evaporated to dryness to give a residue. The crude product was purified by flash chromatography (eluent: methylenechloride/methanol (9/1) to afford Example 10a as an orange powder.

Yield=57% (12.6 g; 37 mmol).

¹H-NMR (DMSO-d₆) δ: 7.0 (m, 3H), 6.75 (broad d, 1H), 6.65 (broad d, 2H), 6.5 (broad s, 1H), 3.4 (s, 2H), 2.8 (s, 1H).

MS: 341 (M−1).

E—Synthesis of Compound I (q is 0)—Scheme B, Route A

Example 11

Compound I wherein Ar is 3,4-DiClPhenyl, X is O, q is 0, substitution in para position, Y—R¹ is CH₂CO-1-(4-acetyl)-piperazinyl.

To a cooled solution of Example 1 (2.27 g; 6.6 mmol) in CH₂Cl₂ (50 mL), N-acetylpiperazine (0.94 g; 7.3 mmol) and EDCI (1.4 g; 7.3 mmol) were added. The reaction mixture was stirred until no more starting material was detected. The organic layer was washed with 1N HCl, water, dried (MgSO₄) and concentrated in vacuo. The crude product was purified by column chromatography (eluent: methylenechloride/methanol 98.5/1.5) to produce Example 11 as an oil.

Yield=76% (2.3 g; 5 mmol)

R_(f)=0.26 (eluent: 96:4 methylenechloride/methanol)

The following examples were prepared according to the process as described for example 11:

Example 12

Compound I wherein Ar is Phenyl, X is O, q is 0, substitution in ortho position, Y—R¹ is CH₂ CONH(CH₂)₂OH.

Reagents: Example 5 (0.7 g, 2.6 mmol) and ethanolamine (0.18 g; 2.9 mmol).

Yield=56% (0.46 g; 1.4 mmol)

R_(f)=0.5 (eluent: 90:10 methylenechloride/methanol)

Example 13

Compound I wherein Ar is 3,4-DiClPhenyl, X is O, q is 0, substitution in para position, Y—R¹ is CH₂CO-1-(4-Boc)-piperazinyl.

To a cooled solution of example 1 (8.8 g; 25.6 mmol) in CH₂Cl₂ (150 mL) N-Bocpiperazine (4.8 g; 25.8 mmol), EDCI (4.9 g; 25.6 mmol) and HOBT (3.5 g; 26 mmol) were added. The reaction mixture was stirred until no more starting material was detected. The organic layer was washed with 1N HCl (2×100 mL), water (100 mL), dried (MgSO₄) and concentrated in vacuo. Trituration of the resulting residue with cold Et₂O, filtration and drying under vacuum gave Example 13 as a white solid.

Yield=70% (9 g; 18 mmol)

R_(f)=0.13 (eluent: 99:1 methylenechloride/methanol)

Example 14

Compound I wherein Ar is 3,4-DiClPhenyl, X is O, q is 0, substitution in para position, Y—R¹ is CH₂CO—N-piperazinyl.

To a solution of Example 13 (2 g; 3.9 mmol) in 1,4-dioxane (20 mL), hydrogenchloride in 1,4-dioxane (4N solution; 20 mL) was added. The reaction mixture was stirred for one hour at room temperature, then ether (200 mL) was added. Filtration and drying under vacuum gave a powder which is dissolved in water (100 mL). The aqueous layer was basified with NaOH (1N) and the resulting precipitate was extracted with ether (150 mL). The dried (MgSO₄) organic layer was evaporated to dryness to furnish Example 14 as an oil.

Yield=87% (1.4 g; 3.4 mmol)

¹H-NMR (DMSO-d₆) δ: 9.5 (s, 2H), 7.7 (d, 1H), 7.4 (d, 1H), 7.3 (d, 1H), 7.05 (d, 1H), 6.95 (dd, 1H), 3.75 (s, 2H), 3.7 (broad, 4H), 3.4 (s, 2H), 3.15 (broad, 2H), 3.05 (broad, 2H)

Example 15

Compound I wherein Ar is 3,4-DiClPhenyl, X is O, q is 0, substitution in ortho position, Y—R¹ is CH₂CONH₂.

To a cold solution of Example 2 (3 g, 8.7 mmol) in methanol (50 mL), thionylchloride (4.2 ml; 57 mmol) was added dropwise. After 1 hour stirring at room temperature, the solvent was removed in vacuo. The oily residue was taken by mixture of MeOH (50 mL) and 28% NH₄OH (50 mL) and the reaction mixture stirred overnight. The methanol was evaporated and water (200 mL) added. The precipitated solid was filtered, washed with water (4×50 mL) and dried in vacuo to generate Example 15 as an off-white solid.

Yield=77% (2.3 g; 6.7 mmol).

R_(f)=0.38 (eluent: 95:5 methylenechloride/methanol).

Example 16

Compound I wherein Ar is 4-ClPhenyl, X is S, q is 0, substitution in para position, Y—R¹ is CH₂CO-1-(4-acetyl)-piperazinyl.

To a cooled solution of Example 3 (2.14 g; 6.6 mmol) in CH₂Cl₂ (50 mL), N-acetylpiperazine (0.9 g; 7 mmol), EDCI (1.4 g; 7.3 mmol) and HOBT (1 g; 7.4 mmol) were added. The reaction mixture was stirred until no more starting material was detected. The organic layer was washed with 1N HCl (2×100 mL), water (100 mL), dried (MgSO₄) and concentrated in vacuo. Trituration of the resulting residue with Et₂O, filtration and drying under vacuum gave Example 16 as a white powder.

Yield=74% (2.15 g; 4.9 mmol)

R_(f)=0.27 (eluent: 95:5 methylenechloride/methanol).

Example 17

Compound I wherein Ar is 4-ClPhenyl, R² is 3-Cl, X is O, q is 0, substitution in para position, Y—R¹ is CH₂CO-1-(4-acetyl)-piperazinyl.

To a cooled solution of Example 6 (3.18 g; 9.3 mmol) in CH₂Cl₂ (60 mL), N-acetylpiperazine (1.33 g; 10.4 mmol), EDCI (2 g; 10.4 mmol) and HOBT (1.41 g; 10.4 mmol) were added. The reaction mixture was stirred until no more starting material was detected. The organic layer was washed with 1N HCl, water, dried (MgSO₄) and concentrated in vacuo. The crude product was purified by column chromatography (eluent: methylenechloride/methanol 98/2) to produce Example 17 as an oil.

Yield=75% (1.6 g; 3.5 mmol)

R_(f)=0.33 (eluent: 95:5 methylenechloride/methanol)

Example 18

Compound I wherein Ar is 4-ClPhenyl, R² is 3-Cl, X is O, q is 0, substitution in para position, Y—R¹ is CH₂CONH2.

To a cooled solution of Example 6 (3.6 g; 10.5 mmol) in methanol (100 mL), thionylchloride (2.2 ml; 30 mmol) was added dropwise. After 1 hour stirring at room temperature, the solvent was removed in vacuo. The oily residue was taken by mixture of MeOH (75 mL) and 28% NH₄OH (75 mL) and the reaction mixture stirred overnight. The methanol was evaporated and water (200 mL) added. The precipitated solid was filtered, washed with water (2×50 mL) and purified by column chromatography (eluent: methylenechloride/methanol 98/2) to produce Example 18 as a white solid.

Yield=58% (2.07 g; 6.0 mmol).

R_(f)=0.52 (eluent: 95:5 methylenechloride/methanol).

Example 18a

Compound I wherein Ar is 4-ClPhenyl, X is O, R² is 4′-Cl, R³ is H, q is 0, substitution in ortho position, Y—R¹ is CH₂CONH₂

To a cold solution of Example 10a (6.3 g, 18.3 mmol) in methanol (100 mL), thionylchloride (3.8 ml; 52 mmol) was added dropwise. After 1 hour stirring at room temperature, the solvent was removed in vacuo. The oily residue was taken by mixture of MeOH (100 mL) and 28% NH₄OH (100 mL) and the reaction mixture stirred overnight. The methanol was evaporated and the residue was purified by flash chromatography (eluent: methylenechloride/methanol (95/5) to afford Example 18a as a white powder.

Yield=56% (3.5 g; 10.2 mmol).

R_(f)=0.44 (eluent: 95:5 methylenechloride/methanol).

F—Preparation of Compound I (q is 1 or 2) Scheme B, Route A

Example 19 2-[4-(3,4-Dichloro-phenoxy)-phenylmethanesulfinyl]-1-piperazin-1-yl-ethanone

Compound I wherein Ar is 3,4-DiClPhenyl, X is O, q is 1, substitution in para position, Y—R¹ is CH₂CO—N-piperazinyl

To a solution of Example 14 (1.4 g; 3.4 mmol) in acetic acid (10 mL), a 30% by wt hydrogen peroxide solution (0.4 mL; 4 mmol) was added. The mixture was stirred until no more starting material was detected (HPLC), concentrated under high vacuum. Then water (100 mL) was added to the residue. The aqueous solution was basified with NaOH (1N) and the precipitate extracted with ethyl acetate (150 mL). The organic phase was dried over MgSO4 and evaporated to dryness to give an oil. Ethanol (30 mL) was added and the solution stirred before adding fumaric acid (0.11 g; 0.95 mmol). The reaction mixture was stirred overnight and filtered. The resulting solid was dried under vacuum to give Example 19.

Yield=38% (0.63 g; 1.3 mmol).

¹H-NMR (DMSO-d₆) δ: 7.7 (d, 1H), 7.4 (d, 2H), 7.3 (d, 1H), 7.2 (d, 2H), 7.1 (dd, 1H), 6.5 (s, 1H), 4.25 (d, 1H), 4.05 (d, 1H), 3.9 (m, 2H), 3.5 (broad, 4H), 2.9 (broad, 4H).

MS: 427 (M+H)

According to the oxidation procedure as described for example 19, the following compounds were prepared:

Example 20 2-[4-(3,4-Dichloro-phenoxy)-phenylmethanesulfinyl]-acetamide

Compound I wherein Ar is 3,4-DiClPhenyl, X is O, q is 1, substitution in ortho position, Y—R¹ is CH₂CONH₂.

Reagent: Example 15 (2.3 g; 6.7 mmol) and a 30% by wt hydrogen peroxide (0.7 mL; 6.9 mmol).

Yield=79% (1.9 g; 5.3 mmol).

¹H-NMR (DMSO-d₆) δ: 7.7 (broad s, 1H), 7.65 (d, 1H), 7.5 (broad d, 1H), 7.40 (broad t, 1H), 7.35 (broad s, 1H), 7.25 (broad s, 1H), 7.20 (t, 1H), 7.0 (broad, 2H), 4.30 (d, 1H), 4.05 (d, 1H), 3.75 (d, 1H), 3.55 (d, 1H).

MS: 358 (M+H)

Example 20a

Compound I wherein Ar is 3,4-DiClPhenyl, X is O, q is 1, (−) enantiomer, substitution in ortho position, Y—R¹ is CH₂CONH₂

The two enantiomers of Example 20 were separated by LC-Prep.

The HPLC analysis was performed as described here:

Column Chiralpak AS (10 μm, 250×4.6 mm, D068)

Mobile phase: Methanol/ethanol 1/1

Flow rate 0.5 mL/min

UV detection 220 nm

Retention time: 8.8 min

Optical rotation [α_(D)]²⁰=−47.

Example 20b

Compound I wherein Ar is 3,4-DiClPhenyl, X is O, q is 1, (+) enantiomer, substitution in ortho position, Y—R1 is CH₂CONH₂

The two enantiomers of Example 20 were separated by LC-Prep.

The HPLC analysis was performed as described here:

Column Chiralpak AS (10 μm, 250×4.6 mm, D068)

Mobile phase: Methanol/ethanol 1/1

Flow rate 0.5 mL/min

UV detection 220 nm

Retention time: 10.9 min

Optical rotation [α_(D)]²⁰=+43.

Example 21 N-(2-Hydroxy-ethyl)-2-(2-phenoxy-phenylmethanesulfinyl)-acetamide

Compound I wherein Ar is Phenyl, X is O, q is 1, substitution in ortho position, Y—R¹ is CH₂ CONH(CH₂)₂OH.

Reagents: Example 12 (0.46 g, 1.45 mmol) and a 30% by wt hydrogen peroxide solution (0.18 mL; 1.8 mmol).

Yield=62% (0.3 g; 0.9 mmol).

¹H-NMR (DMSO-d₆) δ: 8.25 (t, 1H), 7.45-7.25 (m, 4H), 7.2 (t, 2H), 7.0 (d, 2H), 6.8 (d, 1H), 4.7 (t, 1H), 4.3 (d, 1H), 4.05 (d, 1H), 3.75 (d, 1H), 3.6 (d, 1H), 3.4 (q, 2H), 3.2 (m, 2H).

MS: 356 (M+Na)

Example 22 1-(4-Acetyl-piperazin-1-yl)-2-[4-(3,4-dichloro-phenoxy)-phenylmethanesulfinyl]-ethanone

Compound I wherein Ar is 3,4-DiClPhenyl, X is O, q is 1, substitution in para position, Y—R¹ is CH₂CO-1-(4-acetyl)-piperazinyl).

Reagents: Example 11 (2.3 g, 5.1 mmol) and a 30% by wt hydrogen peroxide solution (0.6 mL; 5.9 mmol).

Yield=84% (2 g; 4.3 mmol).

¹H-NMR (DMSO-d₆) δ: 7.65 (d, 1H), 7.4 (d, 2H), 7.3 (broad s, 1H), 7.1 (d, 2H), 7.0 (broad d, 1H), 4.25, (d, 1H), 4.1 (d, 1H), 4.0 (m, 2H), 3.6-3.35 (broad, 8H), 2.0 (s, 3H).

MS: 469 (M+H).

Example 23 1-(4-Acetyl-piperazin-1-yl)-2-[4-(4-chloro-phenylsulfanyl)-phenylmethanesulfinyl]-ethanone

Compound I wherein Ar is 4-ClPhenyl, X is S, q is 1, substitution in para position, Y—R¹ is CH₂CO-1-(4-acetyl)-piperazinyl).

Reagents: Example 16 (1 g; 2.3 mmol), 30% by wt hydrogen peroxide solution (0.25 mL; 2.5 mmol).

Yield=61% (0.65 g; 1.4 mmol of Example 23 as a powder)

¹H-NMR (DMSO-d₆) δ: 7.45 (broad d, 2H), 7.3 (m, 6H), 4.25 (d, 1H), 4.05 (d, 1H), 3.95 (m, 2H), 3.5 (broad, 8H), 2 (s, 3H).

MS: 473 (M+Na).

Example 24 1-(4-Acetyl-piperazin-1-yl)-2-[4-(4-chloro-benzenesulfinyl)-phenylmethanesulfinyl]-ethanone

Compound I wherein Ar is 4-ClPhenyl, X is SO, q is 1, substitution in para position, Y—R¹ is CH₂CO-1-(4-acetyl)-piperazinyl.

Reagents: Example 16 (1 g, 2.3 mmol), a 30% by wt hydrogen peroxide solution (0.25 mL; 2.5 mmol).

Yield=19% (0.2 g; 0.43 mmol of Example 24 as a powder).

¹H-NMR (DMSO-d₆) δ: 7.75 (broad d, 4H), 7.7 (d, 2H), 7.5 (d, 2H), 4.3 (d, 1H), 4.1 (d, 1H), 4.0 (broad s, 2H), 3.4 (broad, 8H), 2.05 (s, 3H).

MS: 489 (M+Na).

Example 25 1-(4-Acetyl-piperazin-1-yl)-2-[2-chloro-4-(4-chloro-phenoxy)-phenylmethanesulfinyl]-ethanone

Compound I wherein Ar is 4-ClPhenyl, R² is 3-Cl, X is O, q is 1, substitution in para position, Y—R¹ is CH₂CO-1-(4-acetyl)-piperazinyl;

To a solution of Example 17 (3.15 g; 6.9 mmol) in acetic acid (20 mL), a 30% by wt hydrogen peroxide solution (0.82 mL; 8.1 mmol) was added. The mixture was stirred until no more starting material was detected (HPLC), and then concentrated under high vacuum. The resulting residue was taken into a mixture of water solution of sodium bicarbonate (200 mL) and ethyl acetate (200 mL). The organic layer was washed with water (1×100 mL), dried over MgSO₄ and concentrated in vacuo to afford compound 25 as a white powder.

Yield=83% (2.7 g; 5.8 mmol).

¹H-NMR (DMSO-d₆) δ: 7.5 (dd, 2H), 7.3 (m, 2H), 7.1 (dd, 2H), 6.8 (broad, 1H), 4.5 (d, 1H), 4.3 (d, 1H), 4.2 (m, 2H), 3.5 (broad, 8H), 2 (s, 3H).

MS: 469 (M+H).

Example 26 2-[2-Chloro-4-(4-chloro-phenoxy)-phenylmethanesulfinyl]-acetamide

Compound I wherein Ar is 4-ClPhenyl; R² is 3-Cl, X is O, q is 1, substitution in para position, Y—R¹ is CH₂CONH2.

Reagents: Example 18 (2.07 g; 6.0 mmol) and a 30% by wt hydrogen peroxide (0.7 mL; 6.9 mmol).

Yield=91% (1.95 g; 5.4 mmol).

¹H-NMR (DMSO-d₆) δ: 7.75 (broad s, 1H), 7.5 (broad d, 2H), 7.3 (m, 3H), 7.15 (broad d, 2H), 6.8 (broad m, 1H), 4.35 (d, 1H), 4.30 (d, 1H), 3.8 (d, 1H), 3.6 (d, 1H).

MS: 380 (M+Na).

Example 27 1-(4-Acetyl-piperazin-1-yl)-2-[4-(3,4-dichloro-phenoxy)-phenylmethanesulfonyl]-ethanone

Compound I wherein Ar is 3,4-DiClPhenyl, X is O, q is 2, substitution in para position, Y—R¹ is CH₂CO-1-(4-acetyl)-piperazinyl;

To a solution of Example 22 (0.85 g; 1.8 mmol) in acetic acid (20 mL), a 30% by wt hydrogen peroxide solution (0.56 mL; 5.5 mmol) was added. The mixture was stirred at 55° C. until no more starting material was detected (HPLC), and then concentrated under high vacuum. The resulting residue was taken into a mixture of water solution of sodium bicarbonate (200 mL) and ethyl acetate (200 mL). The organic layer was washed with water (1×100 mL), dried over MgSO₄ and concentrated in vacuo. The resulting residue was purified by column chromatography (eluent: methylenechloride/methanol 95/5) to generate Example 27 as a white powder.

Yield=71% (0.62 g; 1.3 mmol).

¹H-NMR (DMSO-d₆) δ: 7.7 (d, 1H), 7.45 (d, 2H), 7.30 (broad s, 1H), 7.1 (d, 2H), 7.0 (broad d, 1H), 4.7 (s, 2H), 4.35 (broad d, 2H), 3.6-3.4 (broad m, 8H), 2 (s, 3H).

MS: 507 (M+Na).

Example 27a

Compound I wherein Ar is 4-ClPhenyl, X is O, R² is 4′-Cl, R³ is H, q is 1, substitution in ortho position, Y—R¹ is CH₂CONH₂

To a solution of Example 10a (3.5 g; 10.2 mmol) in acetic acid (30 mL), a 30% by wt hydrogen peroxide solution (1.36 mL; 13.3 mmol) was added. The mixture was stirred until no more starting material was detected (HPLC), and then concentrated under high vacuum. The residue was triturated in diethyloxide the resulting precipitated solid was filtered off, washed with diethyloxide and dried in vacuo to generate Example 27a as a white powder.

Yield=93% (3.4 g; 9.5 mmol).

¹H-NMR (DMSO-d₆) δ: 7.7 (broad s, 1H), 7.45 (broad m, 3H), 7.3 (broad s, 1H), 7.25 (broad d, 1H), 7.1 (broad d, 2H), 6.9 (broad s, 1H), 4.30 (d, 1H), 4.05 (d, 1H), 3.75 (d, 1H), 3.5 (d, 1H).

MS: 379.8 (M+Na).

Example 27b

Compound I wherein Ar is 4-ClPhenyl, X is O, R² is 4′-Cl, R³ is H, q is 2, substitution in ortho position, Y—R¹ is CH₂CONH₂

To a solution of Example 27a (0.07 g; 0.2 mmol) in acetic acid (5 mL), a 30% by wt hydrogen peroxide solution (0.085 mL; 0.8 mmol) was added. The mixture was stirred at 55° C. until no more starting material was detected (HPLC), and then cooled to room temperature. The resulting precipitated solid was filtered off, washed with diethyl oxide and dried in vacuo to generate Example 27b as a white powder.

Yield=65% (0.48 g; 0.13 mmol).

¹H-NMR (DMSO-d₆) δ: 7.8 (broad s, 1H), 7.5 (broad m, 4H), 7.25 (broad d, 1H), 7.1 (broad d, 2H), 6.8 (broad s, 1H), 4.75 (s, 2H), 4.1 (s, 2H).

MS: 396 (M+Na).

G—Synthesis of Compounds I (q is 0, 1, 2)—Scheme B—Route B

Example 28

Compound I wherein Ar is Phenyl, X is O, q is 1, substitution in para position, Y—R¹ is CH₂ COOH.

To a solution of Example 4 (4 g; 14.6 mmol) in acetic acid (30 mL) a 30% by wt hydrogen peroxide solution (1.9 mL; 18 mmol) was added. The mixture was stirred until no more starting material was detected (HPLC), concentrated at high vacuum and triturated with ether to give Example 28 as an off-white solid.

Yield=82% (3.5 g; 12 mmol)

R_(f)=0.15 (eluent: 90:10 methylenechloride/methanol)

Example 29 N-Isopropropyl-2-(4-phenoxy-phenylmethanesulfinyl)-acetamide

Compound I wherein Ar is Phenyl, X is O, q is 1, substitution in para position, Y—R¹ is CH₂CONHCH(CH₃)₂.

To a cooled solution of Example 28 (0.4 g; 1.4 mmol) in CH₂Cl₂ (25 mL), isopropylamine (0.095 g; 1.6 mmol), EDCI (0.31 g; 1.6 mmol) and HOBT (0.22 g; 1.6 mmol) were added. The reaction mixture was stirred until no more starting material was detected. Methylene chloride (100 mL) was added to the reaction mixture and the organic layer washed with 1N HCl (2×100 mL), water (100 mL), dried (MgSO₄) and concentrated in vacuo. The resulting residue was purified by column chromatography (eluent methylenechloride/methanol (93/7) to generate Example 29 as a powder.

Yield=63% (0.35 g; 1 mmol).

¹H-NMR (DMSO-d₆) δ: 8.15 (d, 1H), 7.45 (broad t, 2H), 7.35 (broad d, 2H), 7.15 (broad t, 1H), 7.0 (broad t, 4H), 4.2 (d, 1H), 3.95 (d, 1H), 3.85 (m, 1H), 3.55 (d, 1H), 3.45 (d, 1H), 1.0 (d, 6H).

MS: 354 (M+Na).

Example 30 [4-(3,4-Dichloro-phenoxy)-phenylmethanesulfinyl]-acetic acid

Compound I wherein Ar is 3,4-DiClPhenyl, X is O, q is 1, substitution in para position, Y—R¹ is CH₂COOH.

To a solution of Example 1 (0.94 g; 2.7 mmol) in acetic acid (20 mL) a 30% by wt hydrogen peroxide solution (0.32 mL; 3.2 mmol) was added. The mixture was stirred until no more starting material was detected (HPLC), concentrated at high vacuum and triturated with ether to give Example 30 as an off-white solid.

Yield=57% (0.55 g; 1.53 mmol)

¹H-NMR (DMSO-d₆) δ: 7.7 (d, 1H), 7.4-7.3 (m, 3H), 7.35 (broad d, 2H), 7.1 (d, 2H), 7.0 (broad d, 1H), 4.2 (d, 1H), 4.1 (d, 1H), 3.8 (d, 1H), 3.6 (d, 1H).

MS: 381 (M+Na).

Example 30a [2-(3,4-Dichloro-phenoxy)-phenylmethanesulfinyl]-acetic acid

Compound I wherein Ar is 3,4-DiClPhenyl, X is O, q is 1, substitution in ortho position, Y—R1 is CH₂COOH

To a solution of Example 2 (20.58 g, 60 mmol) in glacial acetic acid (60 mL) was added 35% aqueous hydrogen peroxide (6.6 mL) at room temperature. The mixture was stirred until no more starting material was detected (TLC). After 2 h of stirring, the sulfoxyde precipitated; the precipitate was filtered, washed with water and diisopropyl oxide successively, dried under vacuum to yield Example 30a (white powder; 18.36 g)

Yield=85%.

R_(f): 12.25 min.

¹H-NMR (DMSO) δ (ppm): 7.65 (d, 1H) 7.45 (d, 1H), 7.4 (t, 1H), 7.3-7.15 (m, 2H), 7.05-6.9 (m, 2H), 4.25 (d, 1H), 4.1 (d, 1H), 3.9 (d, 1H), 3.65 (d, 1H).

Example 30b [2-(3,4-Dichloro-phenoxy)-phenylmethanesulfonyl]-acetic acid

Compound I wherein Ar is 3,4-DiClPhenyl, X is O, q is 2, substitution in ortho position, Y—R1 is CH₂COOH

To a suspension of Example 30a (1.79 g, 5 mmol) in glacial acetic acid (5 mL) at room temperature was added 35% aqueous hydrogen peroxide (1.5 mL). The mixture was heated to 50° C. for 4 h until no more starting material was detected (HPLC). After concentration, the residue was triturated in water to give a precipitate that was filtered, washed with water and diisopropyl ether successively, dried under vacuum to yield Example 30b (white powder; 0.78 g)

Yield=42%.

R_(f): 13.5 min.

¹H-NMR (DMSO) δ (ppm): 7.6 (d, 1H) 7.5 (d, 1H), 7.4 (t, 1H), 7.3-7.2 (m, 2H), 7.05-6.9 (m, 2H), 4.7 (s, 2H), 4.25 (s, 2H).

MS: 373 (M−H); 749 (2M+H)

Example 30c

Compound I wherein Ar is 3,4-DiClPhenyl, X is O, q is 0, substitution in ortho position, Y—R1 is CH₂COO (1R,2S,5R)Menthyl

To a stirred solution of Example 2 (5 g; 14.6 mmol) in DMF (30 mL), TBTU (o-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate) (7 g; 21.8 mmol), N-methyl morpholine (2.45 mL; 22.2 mmol) and (1R,2S,5R) (−) menthol were added. The reaction mixture was stirred for fifteen hours, and then ethyl acetate (200 mL) and brine (200 mL) were added into it. The resulting organic layer was evaporated and the residue was purified by flash chromatography (eluent: cyclohexane/ethyl acetate (95/5) to afford Example 30c as a yellow oil.

Yield=60% (4.2 g; 8.7 mmol).

¹H-NMR (DMSO-d₆) δ: 7.7 (broad d, 1H), 7.45 (broad d, 1H), 7.30 (broad t, 1H), 7.2 (broad, 2H), 6.95 (broad m, 2H), 4.55 (m, 1H), 3.8 (s, 2H), 3.25 (s, 2H), 1.8 (broad m, 2H), 1.7 (broad m, 2H), 1.45 (broad, 1H), 1.30 (broad t, 1H), 1.0 (broad, 1H), 0.85 (broad t, 8H), 0.70 (d, 3H).

Example 30d

Compound I wherein Ar is 3,4-DiClPhenyl, X is O, q is 1, substitution in ortho position, Y—R1 is CH₂COOH, enantiomer (−).

To a solution of Example 30c (2.09 g; 4.35 mmol) in acetic acid (25 mL), a 30% by wt hydrogen peroxide solution (0.39 mL; 4.4 mmol) was added. The mixture was stirred at room temperature until no more starting material was detected (HPLC), and then the solvent was evaporated. The residue was purified by flash chromatography (eluent: cyclohexane/ethyl acetate (8/2) to afford a mixture of two diastereoisomers which were separated by LC Preparative. The HPLC analysis was performed as described here:

Column AGP-Chiral (5 μm, 150×4. mm)

Mobile phase: (aqueous ammonium acetate 0.1M)/n-Butanol: 98.5/1.5

Flow rate 0.8 mL/min

UV detection 230 nm

Results: Diastereoisomer 1: retention time 8.1 min,

-   -   Diastereosomer 2: retention time 9.7 min.

To a solution of diastereoisomer 2 in methanol (28 mL) and tetrahydrofuran (75 mL), barium hydroxide octahydrate (0.25 g; 0.8 mmol) was added. The mixture was stirred at room temperature until no more starting material was detected (HPLC), and then the solvent was evaporated. Methylene chloride (50 mL) was added into it. The organic layer was washed with water (1×50 mL), dried over MgSO₄ and concentrated in vacuo. The resulting residue was washed with ether to afford a white powder. To a mixture of this powder in water (17 mL) and ethanol (5 mL), an aqueous hydrochloric acid solution (3 mL, 0.5N) was added. The mixture was stirred at room temperature for 6 hours. The resulting precipitated solid was filtered off, washed with water and dried in vacuo to generate Example 30d as a white powder.

Yield=20% (0.317 g; 0.89 mmol).

¹H-NMR (DMSO-d₆) δ: 7.7 (broad d, 1H), 7.45 (broad d, 1H), 7.30 (broad t, 1H), 7.25 (broad m, 2H), 7.0 (broad t, 2H), 4.25 (d, 1H), 4.1 (d, 1H), 3.95 (s, 1H), 3.7 (s, 1H).

Optical rotation [α_(D)]²⁰=−49.

Enantiomeric excess>98%.

Example 30e

Compound I wherein Ar is 3,4-DiClPhenyl, X is O, q is 1, substitution in ortho position, Y—R1 is CH₂COOH, enantiomer (+).

To a solution of diastereoisomer 1 (isolated during the synthesis of Example 30d) in ethanol (5 mL) and water (7.5 mL), sodium hydroxide was added. The mixture was stirred at room temperature until no more starting material was detected (HPLC). Aqueous hydrochloric acid solution (10 mL, 0.5N) and methylene chloride (50 mL) were added into it. The organic layer was washed with water (1×50 mL), dried over MgSO₄ and concentrated in vacuo. The resulting residue was triturated in diethyl oxide and the precipitated solid was filtered off, washed with diethyl oxide and dried in vacuo to generate Example 30e as a white powder.

Yield=16% (0.255 g; 0.71 mmol).

¹H-NMR (DMSO-d₆) δ: 7.7 (broad d, 1H), 7.45 (broad d, 1H), 7.30 (broad t, 1H), 7.25 (broad m, 2H), 7.0 (broad t, 2H), 4.25 (d, 1H), 4.1 (d, 1H), 3.95 (s, 1H), 3.7 (s, 1H).

Optical rotation [α_(D)]²⁰=+46.

Enantiomeric excess>98%.

Example 30f [2-(3,4-Dichloro-phenoxy)-phenylmethanesulfanyl]-N,N-dimethyl-acetamide

Compound I wherein Ar is 3,4-DiClPhenyl, X is O, q is 0, substitution in ortho position, Y—R1 is CH₂CON(CH₃)₂

To a cooled (ice-bath) solution of Example 2 (3.43 g, 10 mmol) in CH₂Cl₂ (60 mL), was added successively dimethylamine (0.495 g, 1.25 mL, 11 mmol), EDCI (2.1 g, 11 mmol) and HOBT (1.48 g, 11 mmol). The cooling bath was removed and the reaction mixture was stirred at room temperature for one night. It was then diluted with CH₂Cl₂ (40 ml), washed successively with water (60 ml), aqueous NaHCO₃, water (60 ml) and dried over Na₂SO₄. On concentration, the solution generated an orange oil that was triturated in diisopropyl ether to yield the title compound Example 30f (2.9 g; beige powder).

Yield=78%.

R_(f) (CH₂Cl₂/CH₃OH 9/1)=0.65.

R_(t): 15.86 min.

Example 30g [2-(3,4-Dichloro-phenoxy)-phenylmethanesulfinyl]-N,N-dimethyl-acetamide

Compound I wherein Ar is 3,4-DiClPhenyl, X is O, q is 1, substitution in ortho position, Y—R1 is CH₂CON(CH₃)₂

To a suspension of Example 30f (2.91 g, 7.9 mmol) in glacial acetic acid (10 mL) at room temperature was added 35% aqueous hydrogen peroxide (0.87 mL). The mixture was stirred for 3 h until no more starting material was detected (HPLC). After concentration, the residue was triturated in diisopropyl ether to give a solid that was filtered, washed with diisopropyl ether and dried under vacuum to yield Example 30g (slightly beige powder; 0.78 g).

Yield=86%.

R_(t): 12.32 min.

¹H-NMR (DMSO) δ (ppm): 7.65 (d, 1H) 7.45 (d, 1H), 7.4 (t, 1H), 7.25-7.2 (m, 2H), 7 (dd, 2H), 4.25 (d, 1H), 4.15 (d, 1H), 3.95 (s, 2H), 2.95 (s, 3H), 2.75 (s, 3H).

MS: 408 (M+Na).

Compounds 31 through 112 were prepared following the same multistep general method as described in scheme B utilizing the appropriate substituted amine —NR¹²R¹³ in steps 5 or 6. The analytical data is presented by each compounds molecular formula and masse spectrum (M+H) or (M+Na) as shown in the following Table 2.

TABLE 2 Example N^(o) Molecular Formula Peak Mass Scheme B, route A 31 C₁₉H₂₁NO₃S M + H 344 32 C₁₅H₁₅NO₃S M + H 290 33 C₁₇H₁₉NO₃S M + H 318 34 C₁₈H₂₁NO₃S M + H 332 35 C₂₁H₂₄N₂O₄S M + H 401 36 C₁₆H₁₇NO₄S M + Na 342 37 C₂₂H₂₆N₂O₅S M + Na 453 38 C₂₀H₂₄N₂O₄S•C₄H₄O₄ M + H 389 39 C₁₅H₁₃Cl₂NO₃S M + Na 380 40 C₂₁H₂₂Cl₂N₂O₄S M + H 469 41 C₂₀H₂₁Cl₂N₃O₄S M + H 470 42 C₁₆H₁₇NO₄S M + Na 342 43 C₁₅H₁₄ClNO₃S M + Na 346 44 C₁₅H₁₅NO₄S M + Na 328 45 C₁₅H₁₄ClNO₃S M + H 324 46 C₂₁H₂₃ClN₂O₄S M + Na 457 47 C₁₉H₂₁ClN₂O₃S•C₄H₄O₄ M + H 393 48 C₂₁H₂₃FN₂O₄S M + H 419 49 C₂₁H₂₃FN₂O₄S M + H 419 50 C₁₅H₁₄FNO₃S M + Na 330 51 C₁₅H₁₄FNO₃S M + Na 330 52 C₁₉H₁₇NO₃S M + Na 362 53 C₂₆H₂₇NO₄S M + Na 473 54 C₁₉H₁₇NO₃S M + Na 362 55 C₂₁H₁₉NO₃S M + Na 388 56 C₂₁H₁₉NO₃S M + H 366 57 C₂₁H₂₃ClN₂O₄S M + H 435 58 C₂₅H₂₆N₂O₄S M + Na 473 59 C₂₇H₂₈N₂O₄S M + H 477 60 C₂₇H₂₈N₂O₄S M + Na 499 61 C₂₁H₂₃ClN₂O₄S M + Na 457 62 C₂₁H₂₆N₂O₄S•HCl M + H 403 63 C₂₂H₂₄Cl₂N₂O₅S M + H 499 64 C₂₁H₂₅FN₂O₄S•HCl M + H 421 65 C₂₁H₂₄Cl₂N₂O₄S•HCl M + H 471 66 C₂₀H₂₃FN₂O₃S•HCl M + H 391 67 C₁₅H₁₄ClNO₃S M + Na 346 68 C₂₂H₂₅FN₂O₅S M + H 449 69 C₂₃H₂₈N₂O₆S M + Na 483 70 C₂₂H₂₅ClN₂O₄S₂ M + Na 503 71 C₂₂H₂₅ClN₂O₅S₂ M + Na 519 72 C₂₂H₂₄Cl₂N₂O₅S M + Na 521 73 C₁₉H₂₁ClN₂O₂S₂ M + H 409 74 C₂₁H₂₂Cl₂N₂O₄S M + Na 491 75 C₂₁H₂₂Cl₂N₂O₄S M + Na 491 76 C₁₅H₁₃Cl₂NO₃S M + Na 380 77 C₁₅H₁₃Cl₂NO₃S M + Na 380 78 C₂₁H₂₂Cl₂N₂O₄S M + Na 491 79 C₂₁H₂₂Cl₂N₂O₄S M + H 469 80 C₁₅H₁₃Cl₂NO₃S M + Na 380 81 C₁₅H₁₃Cl₂NO₃S M + H 358 82 C₂₁H₂₂Cl₂N₂O₄S M + H 469 83 C₂₁H₂₂Cl₂N₂O₄S M + H 469 84 C₁₅H₁₃Cl₂NO₃S M + Na 380 85 C₁₅H₁₃Cl₂NO₃S M + H 358 86 C₂₁H₂₂Cl₂N₂O₄S M + H 469 87 C₂₁H₂₂Cl₂N₂O₃S₂ M + H 485 88 C₁₅H₁₃Cl₂NO₃S M + Na 380 89 C₁₅H₁₃Cl₂NO₂S₂ M + Na 396 90 C₂₁H₂₂Cl₂N₂O₄S M + Na 491 91 C₂₁H₂₂Cl₂N₂O₄S M + Na 491 92 C₁₅H₁₃Cl₂NO₃S M + Na 380 93 C₁₅H₁₃Cl₂NO₄S M + Na 396 94 C₁₅H₁₃Cl₂NO₃S M + Na 380 95 C₂₁H₂₃FN₂O₅S M + Na 457 96 C₂₁H₂₂Cl₂N₂O₅S M + Na 507 97 C₁₅H₁₅NO₃S M + H 290 98 C₁₉H₂₁NO₃S M + H 344 99 C₁₇H₁₉NO₃S M + H 318 100  C₁₇H₁₉NO₃S M + H 318 101  C₁₉H₂₁NO₃S M + H 344 102  C₁₅H₁₅NO₃S M + Na 312 103  C₁₇H₁₆N₂O₃S M + Na 351 104  C₁₈H₂₁NO₃S M + H 332 105  C₁₉H₂₃NO₃S M + H 346 106  C₂₀H₂₃NO₄S M + H 374 107  C₂₁H₂₄N₂O₄S M + Na 423 108  C₁₇H₁₉NO₄S M + H 334 109  C₂₀H₂₃NO₄S M + H 374 109a C₁₅H₁₄ClNO₃S M + Na 346 109b C₁₅H₁₃ClFNO₃S M + Na 364 109c C₁₅H₁₃ClFNO₃S M + Na 364 109d C₁₅H₁₃ClFNO₄S M + Na 380 109e C₁₅H₁₂ClF2NO₃S M + Na 381.8  109f C₁₅H₁₃Cl₂NO₄S M + Na 395.7 Scheme B, route B 110  C₂₁H₂₄N₂O₄S M + Na 423 111  C₁₇H₁₉NO₄S M + Na 356 112  C₂₀H₂₃NO₄S M + Na 396 112a C₁₆H₁₅Cl₂NO₃S M + Na 394 2M + Na 766 112b C₁₉H₂₁Cl₂NO₃S M + Na 436 2M + Na 851 II—Compounds Prepared According to Scheme C.

Examples 113 to 149 were synthesized according to Scheme C.

A—Preparation of Compound J

Compound 12

Compound J wherein Y—R¹ is CH₂COOCH₃, NO₂ is in ortho position, R² and R³ are H.

To a stirred solution of 2-nitrobenzyl bromide (43.2 g; 200 mmol) in dry acetone (200 mL), methylthioglycolate (19 ml; 212 mmol), potassium iodide (0.2 g; 1.2 mmol) and potassium carbonate (27.6 g; 200 mmol) were added. The reaction mixture was refluxed for 4 hours and then the solvent removed. The resulting residue was taken into a mixture of water (500 mL) and ether (500 mL). The organic layer was washed with water, dried over MgSO₄ and concentrated in vacuo to give compound 12 as an orange oil.

Yield: 100% (48.2 g; 199.9 mmol)

R_(f)=0.55 (eluent: methylenechloride)

Compound 13

Compound J wherein Y—R¹ is CH₂COOH, NO₂ is in ortho position, R² and R³ are H.

To a stirred solution of 2-nitrobenzyl bromide (25 g; 116 mmol) in dry acetone (100 mL), thioglycolic acid (8.5 mL; 122 mmol), potassium iodide (0.09 g; 0.5 mmol) and potassium carbonate (17.5 g; 127 mmol) were added. The reaction mixture was refluxed overnight and the solvent was removed. The resulting residue was taken into water (500 mL) and the cooled aqueous mixture acidified with hydrochloric acid 4N to pH 2. The precipitate was extracted with ethylacetate (500 mL) and the organic layer washed with water (2×200 mL), dried over MgSO4 and concentrated in vacuo to furnish an oil that was purified by column chromatography (eluent: methylenechloride/methanol (9/1) to afford compound 13 as a yellow powder after solvent evaporation.

Yield: 76% (19.9 g; 88 mmol).

R_(f)=0.35 (eluent: 9:1 methylenechloride:methanol).

Compound 13a

Compound J wherein Y—R¹ is CH₂COOCH₃, NO₂ is in para position, R² and R³ are H.

To a stirred solution of 4-nitrobenzyl bromide (43.2 g; 200 mmol) in dry acetone (200 mL), methylthioglycolate (19 mL; 212 mmol), potassium iodide (0.2 g; 1.2 mmol) and potassium carbonate (27.6 g; 200 mmol) were added. The reaction mixture was refluxed for 4 hours and then the solvent removed. The resulting residue was taken into a mixture of water (500 mL) and ether (500 mL). The organic layer was washed with water, dried over MgSO₄ and concentrated in vacuo to give compound 13a as an orange oil.

Yield: 100% (48.2 g; 199.9 mmol)

R_(f)=0.95 (eluent: 9:1 methylenechloride/methanol)

B—Preparation of Compound K

Compound 14

Compound K wherein Y—R¹ is CH₂CONH₂, NO₂ is in ortho position, R² and R³ are H.

To a stirred solution of compound 12 (20 g, 82.9 mmol) in methanol (50 mL), 28% NH₄OH (50 mL) was added. The reaction mixture was stirred overnight, the methanol evaporated and water (250 mL) added into the mixture. The precipitated solid was filtered off, washed with water and dried in vacuo to generate compound 14 as a yellow powder.

Yield: 81% (15.1 g; 67 mmol)

R_(f)=0.28 (eluent: 95:5 methylenechloride/methanol)

Compound 15

Compound K wherein Y—R¹ is CH₂CO-1-(4-acetyl)-piperazinyl, NO₂ is in ortho position, R² and R³ are H.

To a cooled solution of compound 13 (12 g, 53 mmol) in CH₂Cl₂ (200 mL), N-acetylpiperazine (7.3 g; 57 mmol), EDCI (10.9 g; 57 mmol) and HOBT (7.8 g; 58 mmol) were added. The reaction mixture was stirred until no more starting material was detected. The organic layer was washed with 1N HCl (2×100 mL), water (100 mL), dried (MgSO₄) and concentrated in vacuo. Trituration of the resulting residue with Et₂O, filtration and drying under vacuum gave compound 15 as an off-white solid.

Yield: 92% (16.4 g; 49 mmol).

R_(f)=0.23 (eluent: 97:3 methylenechloride/methanol).

Compound 15a

Compound K wherein Y—R¹ is CH₂CONH₂, NO₂ is in para position, R² and R³ are H.

To a stirred solution of compound 13a (48.2 g, 200 mmol) in methanol (250 mL), 28% NH₄OH (250 mL) was added. The reaction mixture was stirred overnight, the methanol evaporated and water (700 mL) added into the mixture. The precipitated solid was filtered off, washed with water and dried in vacuo to generate compound 15a as an orange powder.

Yield: 78% (35.5 g; 157 mmol)

R_(f)=0.55 (eluent: 9:1 methylenechloride/methanol).

C—Preparation of Compound L

Compound 16

Compound L wherein Y—R¹ is CH₂CONH₂, q is 1, NO₂ is in ortho position, R² and R³ are H.

To a solution of compound 14 (8 g; 35.4 mmol) in acetic acid (120 mL), a 30% by wt hydrogen peroxide solution (4.5 mL; 40 mmol) was added. The reaction mixture was stirred overnight and concentrated under high vacuum. Trituration of the resulting residue with ethylacetate, filtration and drying under vacuum gave compound 16 as a yellow powder.

Yield: 90% (7.86 g; 32 mmol).

R_(f)=0.34 (eluent: 9:1 methylenechloride/methanol).

Compound 17

Compound L wherein Y—R¹ is CH₂CO-1-(4-acetyl)-piperzinyl, q is 1, NO₂ is in ortho position, R² and R³ are H.

To a solution of compound 15 (8.2 g; 24.3 mmol) in acetic acid (60 mL), a 30% by wt hydrogen peroxide solution (2.8 mL; 28 mmol) was added. The reaction mixture was stirred for two hours and concentrated at high vacuum. The resulting residue was purified by column chromatography (eluent: with methylenechloride/methanol (9/1) to afford compound 17 as a yellow powder.

Yield: 74% (6.4 g; 18 mmol).

R_(f)=0.40 (eluent: 9:1 methylenechloride/methanol).

D—Preparation of Compound M′

Compound 17a

Compound M wherein Y—R¹ is CH₂CONH₂, q is O, NH₂ is in para position, R² and R³ are H.

To a stirred solution of compound 15a (5.5 g, 24 mmol) in acetic acid (60 mL) and water (120 mL), iron (6.7 g, 120 mmol) was added. The reaction mixture was refluxed for 15 minutes. The iron was removed by filtration on a pad of Celite, and the filtrate was evaporated. The resulting residue was purified by column chromatography (eluent methylenechloride/methanol (9/1) to generate compound 17a as a grey powder.

Yield: 71% (3.36 g; 17 mmol).

R_(f)=0.46 (eluent: 9:1 methylenechloride/methanol).

E—Preparation of Compound M

Compound 18

Compound M wherein Y—R¹ is CH₂CONH₂, q is 1, NH₂ is in ortho position, R² and R³ are H.

Compound 16 wherein (7.86 g, 32.5 mmol) in a mixture of DMF (50 mL) and MeOH (50 mL) was reduced in the presence of 10% Pd/C (1.6 g) in an autoclave under hydrogen pressure (50 PSI) for 12 hours. The catalyst was removed by filtration on a pad of Celite, and the filtrate was evaporated. Trituration of the resulting residue with ethylacetate, filtration and drying under vacuum gave compound 18 as an off-white solid.

Yield: 80% (5.6 g; 26 mmol).

R_(f)=0.25 (eluent: 5.6 g; 26 mmol).

Compound 19

Compound M wherein Y—R¹ is CH₂CO-1-(4-acetyl)-piperazinyl, q is 1, NH₂ is in ortho position, R² and R³ are H.

Compound 17 (2.1 g, 5.9 mmol) in MeOH (50 mL) was reduced in the presence of 10% Pd/C (0.2 g) in an autoclave under an hydrogen pressure (50 PSI) for 18 hours. The catalyst was removed by filtration on a pad of Celite, and the filtrate was evaporated. The resulting residue was purified by column chromatography (eluent methylenechloride/methanol (96/4) to generate compound 19 as a white powder.

Yield: 68% (1.3 g; 4 mmol).

R_(f)=0.29 (eluent: 9:1 methylenechloride/methanol).

Compound 19a

Compound M wherein Y—R¹ is CH₂CONH₂, q is 1, NH₂ is in para position, R² and R³ are H.

To a solution of compound 17a (1 g; 5.09 mmol) in acetic acid (15 mL), a 30% by wt hydrogen peroxide solution (0.6 mL; 5.9 mmol) was added. The reaction mixture was stirred for three hours and then diethyloxide was added into the mixture. The precipitated solid was filtered off, washed with diethyloxide and dried in vacuo to generate compound 19a as an yellow powder.

Yield: 65% (0.7 g; 3.3 mmol).

R_(f)=0.20 (eluent: 9:1 methylenechloride/methanol).

F—Preparation of Compound I

Example 113 N-(2-Carbamoylmethanesulfinylmethyl-phenyl)-4-chloro-benzamide

Compound I wherein Ar is 4-ClPhenyl, X is CONH, q is 1, substitution in ortho position, R² and R³ are H, Y—R¹ is CH₂CONH₂.

To a stirred solution of compound 18 (1 g; 4.7 mmol) in CH₂Cl₂ (50 mL) were added pyridine (0.76 mL; 9.4 mmol) and 4-chlorobenzoylchloride (0.6 mL; 4.7 mmol). The reaction mixture was stirred for one hour and filtered. The resulting solid was washed with water and methylenechloride and dried under vacuum to give Example 113 as a solid.

Yield: 81% (1.32 g; 3.8 mmol).

¹H-NMR (DMSO-d₆) δ: 10.6 (s, 1H), 8.0 (broad d, 2H), 7.75 (broad, 2H), 7.6 (broad d, 2H), 7.4 (broad, 3H), 7.25 (broad, 1H), 4.55 (d, 1H), 4.3 (d, 1H), 3.8 (d, 1H), 3.5 (d, 1H).

MS: 373 (M+Na).

The following examples were prepared according to the procedure as described for Example 113.

Example 114 N-(2-Carbamoylmethanesulfinylmethyl-phenyl)-3,4-dimethoxy-benzamide

Compound I wherein Ar is 3,4-DiOCH₃Phenyl, X is CONH, q is 1, substitution in ortho position, R² and R³ are H, Y—R¹ is CH₂CONH₂.

Reagents: compound 18 (1 g; 4.7 mmol) and 3,4-dimethoxybenzoyl chloride (0.94 g; 4.7 mmol). Example 114 is a solid.

Yield: 49% (0.87 g; 2.3 mmol).

¹H-NMR (DMSO-d₆) δ 10.5 (s, 1H), 7.8 (d, 1H), 7.75 (broad, 1H), 7.6 (d, 1H), 7.55 (broad, 1H), 7.35 (broad, 3H), 7.2 (t, 1H), 7.1 (d, 1H), 4.5 (d, 1H), 4.3 (d, 1H), 3.85 (s, 6H), 3.75 (d, 1H).

MS: 399 (M+Na)

Example 115 Naphtalene-2-carboxylic acid (2-carbamoylmethanesulfinylmethyl-phenyl)-amide

Compound I wherein Ar is 2-Naphthyl, X is CONH, q is 1, substitution in ortho position, R² and R³ are H, Y—R¹ is CH₂CONH₂.

Reagents: compound 18 (1 g; 4.7 mmol) and 2-naphthoylchloride (0.92 g; 4.7 mmol). Example 115 is a solid.

Yield: 58% (1 g; 2.7 mmol)

¹H-NMR (DMSO-d₆) δ: 10.75 (s, 1H), 8.7 (s, 1H), 8.1 (m, 3H), 8.05 (d, 1H), 7.8 (d, 1H), 7.75 (s, 1H), 7.60 (m, 2H), 7.45 (m, 3H), 7.30 (t, 1H), 4.55 (d, 1H), 4.30 (d, 1H), 3.8 (d, 1H), 3.55 (d, 1H).

MS: 367 (M+H).

Example 116 N-{2-[2-(4-Acetyl-piperazin-1-yl)-2-oxo-ethanesulfinylmethyl]-phenyl}-4-chloro-benzamide

Compound I wherein Ar is 4-Clph, X is CONH, q is 1, substitution in ortho position, R² and R³ are H, Y—R¹ is CH₂CO-1-(4-acetyl)-piperazinyl.

To a stirred solution of compound 19 (1 g; 3.7 mmol) in CH₂Cl₂ (40 mL), pyridine (0.76 mL; 9.4 mmol) and 4-chlorobenzoylchloride (0.6 mL; 4.7 mmol) were added. The reaction mixture was stirred for one hour and then the solvent was removed. Trituration of the resulting residue with ethylacetate, filtration and drying under vacuum gave Example 116 as a powder.

Yield: 65% (0.92 g; 2 mmol).

¹H-NMR (DMSO-d₆) δ: 10.55 (s, 1H), 8.0 (d, 2H), 7.75 (d, 1H), 7.65 (dd, 2H), 7.45 (m, 2H), 7.25 (t, 1H), 4.45 (m, 1H), 4.35 (m, 1H), 4.2 (d, 1H), 4.1 (d, 1H), 3.45 (broad, 8H), 2.0 (s, 3H).

MS: 484 (M+Na).

Examples 117 through 129 were prepared following the same multistep general method as described for Example 116 utilizing the appropriate substituted amine —NR¹²R¹³ and the appropriate benzoyl chloride in step 4. The analytical data is presented by each compounds molecular formula and masse spectrum (M+H) or (M+Na) as shown in the following Table 3.

TABLE 3 Example N^(o) Molecular Formula Peak Mass 117 C₁₆H₁₄F₂N₂O₃S M + H 353 118 C₁₈H₂₀N₂O₅S M + H 377 119 C₁₉H₂₂N₂O₆S M + H 407 120 C₁₈H₂₀N₂O₅S M + H 377 121 C₂₄H₂₉N₃O₆S M + H 488 122 C₂₄H₂₉N₃O₆S M + H 488 123 C₂₂H₂₄FN₃O₄S M + H 446 124 C₂₂H₂₃Cl₂N₃O₄S M + H 496 125 C₁₈H₂₀N₂O₅S M + H 377 126 C₁₆H₁₅FN₂O₃S M + H 335 127 C₁₆H₁₄Cl₂N₂O₃S M + Na 407 128 C22H23Cl2N3O4S M + Na 518 129 C22H24FN3O4S M + Na 468

Example 130 N-{2-[2-(4-Acetyl-piperazin-1-yl)-2-oxo-ethanesulfinylmethyl]-phenyl}-3,4-dichlorobenzenesulfonamide

Compound I wherein Ar is 3,4-DiClPh, X is SO₂NH, q is 1, substitution in ortho position, R² and R³ are H, Y—R¹ is CH₂CO-1-(4-acetyl)-piperazinyl.

To a stirred solution of compound 19 (1 g; 3.1 mmol) in CH₂Cl₂ (30 mL), pyridine (0.5 mL; 6.2 mmol) and 3,4-Dichlorobenzenesulfonylchloride (0.48 mL; 3.1 mmol) were added. The reaction mixture was stirred for twelve hours and then, methylene chloride (200 mL) were added into it. The resulting mixture was washed with an aqueous hydrochloric acid solution 1N (1×150 mL) and evaporated. The resulting residue was purified by column chromatography (eluent: methylenechloride/methanol 9/1) to generate Example 130 as a white powder.

Yield: 91% (1.5 g; 2.8 mmol).

R_(f)=0.46 (eluent: 9:1 methylenechloride/methanol).

¹H-NMR (DMSO-d₆) δ: 10.1 (s, 1H), 7.85 (broad d, 2H), 7.70 (broad d, 1H), 7.40-7.30 (m, 3H), 7.00 (broad m, 1H), 4.30 (d, 1H), 4.20-4.00 (broad m, 3H), 3.60-3.40 (broad, 8H), 2.0 (s, 3H).

MS: 554 (M+Na).

Examples 131 through 133 were prepared following the same multistep general method as described for Example 130 utilizing the appropriate substituted amine —NR¹²R¹³ and the appropriate sulfonylchloride in step 4. The analytical data is presented by each compounds molecular formula and masse spectrum (M+H) or (M+Na) as shown in the following Table 4:

TABLE 4 Example N^(o) Molecular Formula Peak Mass 131 C₂₁H₂₄FN₃O₅S₂ M + Na 504 132 C₂₁H₂₄ClN₃O₅S₂ M − 1(ESI-) 496 133 C₂₁H₂₃Cl₂N₃O₅S₂ M + Na 554

Example 134 1-(4-Acetyl-piperazin-1-yl)-2-[2-(4-methoxy-phenylamino)-phenylmethanesulfinyl]-ethanone

Compound I wherein Ar is 4-OCH₃Ph, X is NH, q is 1, substitution in ortho position, R² and R³ are H, Y—R¹ is CH₂CO-1-(4-acetyl)-piperazinyl.

To a stirred mixture of 4-methoxyphenyl boronic acid (1 g; 6.6 mmol), myristic acid (0.3 g; 1.3 mmol) and copper(II) acetate anhydrous (0.12 g; 0.66 mmol) in CH₂Cl₂ (10 mL) were added compound 19 (1.4 g; 4.3 mmol) in CH₂Cl₂ (10 mL) and 2,6-lutidine (0.52 mL; 4.5 mmol). The reaction mixture was stirred for two days. The catalyst was removed by filtration on a pad of Celite, and the filtrate was evaporated. The resulting residue was purified by column chromatography (eluent: methylenechloride/methanol 96/4) to generate Example 134 as a beige powder.

Yield: 49% (0.9 g; 2.1 mmol).

R_(f)=0.49 (eluent: 9:1 methylenechloride/methanol).

¹H-NMR (DMSO-d₆) δ: 7.70 (s, 1H), 7.20-7.10 (m, 2H), 7.05 (broad d, 1H), 6.90 (broad d, 2H), 6.85-6.70 (m, 3H), 4.30 (broad dd, 1H), 4.20 (broad d, 1H), 4.05 (broad m, 2H), 3.50 (broad, 8H), 2.00 (s, 3H).

MS: 452 (M+Na).

Examples 135 through 141 were prepared following the same multistep general method as described for Example 134 utilizing the appropriate substituted amine —NR¹²R¹³ and the appropriate substituted boronic acid in step 4. The analytical data is presented by each compounds molecular formula and masse spectrum (M+H) or (M+Na) as shown in the following Table 5.

TABLE 5 Example N^(o) Molecular Formula Peak Mass 135 C₂₁H₂₅N₃O₃S M + Na 422 136 C₂₁H₂₅N₃O₃S M + Na 422 137 C₂₂H₂₇N₃O₄S M + Na 452 138 C₂₁H₂₄FN₃O₃S M + Na 440 139 C₂₁H₂₄ClN₃O₃S M + Na 456 140 C₂₁H₂₄FN₃O₃S M + Na 440 141 C₂₁H₂₃Cl₂N₃O₃S M + Na 490

Example 142 Thiophene-2-carboxylic acid {2-[2-(4-acetyl-piperazin-1-yl)-2-oxo-ethanesulfinylmethyl]-phenyl}-amide

Compound I wherein Ar is 2-Thienyl, X is CONH, q is 1, substitution in ortho position, R² and R³ are H, Y—R¹ is CH₂CO-1-(4-acetyl)-piperazinyl.

To a stirred solution of compound 19 (1 g; 3.1 mmol) in CH₂Cl₂ (30 mL), pyridine (0.5 mL; 6.2 mmol) and 2-thiophenecarbonyl chloride (0.46 g; 3.1 mmol) were added. The reaction mixture was stirred for twelve hours and then, methylene chloride (100 mL) were added into it. The resulting mixture was washed with an aqueous hydrochloric acid solution 1N (2×100 mL) and evaporated. The resulting residue was purified by column chromatography (eluent: methylenechloride/methanol 9/1) to generate Example 142 as a white powder.

Yield: 86% (1.16 g; 2.7 mmol).

R_(f)=0.50 (eluent: 9:1 methylenechloride/methanol).

¹H-NMR (DMSO-d₆) δ: 10.55 (s, 1H), 7.80 (broad d, 2H), 7.75 (broad d, 1H), 7.45-7.30 (m, 2H), 7.25-7.15 (m, 2H), 4.45 (broad, 2H), 4.20-4.00 (broad m, 2H), 3.50-3.40 (broad, 8H), 2.0 (s, 3H).

MS: 456 (M+Na).

Example 143 was prepared following the same multistep general method as described for Example 142 utilizing the appropriate substituted amine —NR¹²R¹³ and the appropriate carbonyl chloride in step 4. The molecular formula and masse spectrum (M+H) or (M+Na) are presented for Example 143 in Table 6.

TABLE 6 Example N^(o) Molecular Formula Peak Mass 143 C₂₀H₂₃N₃O₅S M + Na 440

Example 144 1-(4-Acetyl-piperazin-1-yl)-2-{2-[(thiophen-2-ylmethyl)-amino]-phenylmethanesulfinyl}-ethanone

Compound I wherein Ar is 2-Thienyl, X is CH₂NH, q is 1, substitution in ortho position, R² and R³ are H, Y—R¹ is CH₂CO-1-(4-acetyl)-piperazinyl.

To a cooled solution of compound 19 (0.65 g; 2 mmol) in 1,2-dichloroethane (10 mL), 2-thiophene carboxaldehyde (0.29 g; 2.6 mmol), sodium triacetoxy borohydride (0.57 g; 2.7 mmol) and acetic acid (0.15 mL) were added. The reaction mixture was stirred under nitrogen for three hours and then, ethylacetate (100 mL) were added into it. The resulting mixture was washed with an aqueous sodium hydrogenocarbonate (1×100 mL), aqueous solution (1×100 mL) and evaporated. The resulting residue was purified by column chromatography (eluent: methylenechloride/methanol 9/1) to generate Example 144 as a white powder.

Yield: 71% (0.6 g; 1.4 mmol).

R_(f)=0.45 (eluent: 9:1 methylenechloride/methanol).

¹H-NMR (DMSO-d₆) δ: 7.40 (broad d, 1H), 7.20-7.00 (m, 3H), 6.85-6.95 (broad m, 1H), 6.7-6.6 (broad m, 2H), 6.30 (broad, 1H), 4.50 (broad d, 1H), 4.30 (broad d, 1H), 4.20-4.00 (broad m, 3H), 3.55-3.45 (broad, 8H), 2.00 (s, 3H).

MS: 442 (M+Na).

Example 145 was prepared following the same multistep general method as described for Example 144 utilizing the appropriate substituted amine —NR¹²R¹³ and the appropriate aldehyde in step 4. The molecular formula and masse spectrum (M+H) or (M+Na) is presented for Example 145 in Table 7.

TABLE 7 Example N^(o) Molecular Formula Peak Mass 145 C₂₀H₂₅N₃O₄S M + Na 426

Example 146 1-(4-Acetyl-piperazin-1-yl)-2-[2-(3,4-dichloro-benzylamino)-phenylmethanesulfinyl]-ethanone

Compound I wherein Ar is 3,4-DiClPh, X is CH₂NH, q is 1, substitution in ortho position, R² and R³ are H, Y—R¹ is CH₂CO-1-(4-acetyl)-piperazinyl.

To a stirred solution of compound 19 (1 g; 3.1 mmol) in DMF (25 mL), diisopropylethylamine (0.6 mL; 3.4 mmol) and 3,4-dichlorobenzyl bromide (0.74 g; 3.1 mmol) were added. The reaction mixture was stirred for twelve hours and then, ethylacetate (250 mL) were added into it. The resulting mixture was washed with brine (2×200 mL) and evaporated. The resulting residue was purified by column chromatography (eluent: methylenechloride/methanol 9/1) to generate Example 146 as a white powder.

Yield: 51% (0.76 g; 1.6 mmol).

R_(f)=0.47 (eluent: 9:1 methylenechloride/methanol).

¹H-NMR (DMSO-d₆) δ: 7.70 (broad s, 1H), 7.60 (broad d, 1H), (broad m, 1H), 7.4 (broad d, 1H), 7.10 (broad m, 2H), 6.6 (broad t, 1H), 6.5 (broad d, 1H), 6.3 (broad m, 1H), 4.4-4.3 (broad m, 3H), 4.2-4.0 (broad, 3H), 3.55-3.35 (broad, 8H), 2.0 (s, 3H).

MS: 504 (M+Na).

Examples 147 through 149 were prepared following the same multistep general method as described for Example 146 utilizing the appropriate substituted amine —NR¹²R¹³ and the appropriate benzyl halide in step 4. The molecular formula and masse spectrum (M+H) or (M+Na) are presented for each Examples in Table 8.

TABLE 8 Example N^(o) Molecular Formula Peak Mass 147 C₂₂H₂₆FN₃O₃S M + Na 454 148 C₂₂H₂₅Cl₂N₃O₃S M + Na 504 149 C₂₂H₂₆FN₃O₃S M + Na 454

Example 149a

Compound I wherein Ar is 3,4-DiClPhenyl, X is CONH, q is 1, substitution in para position, R² and R³ are H, Y—R¹ is CH₂CONH₂.

To a stirred solution of compound 19a (0.7 g; 3.3 mmol) in CH₂Cl₂ (30 mL) were added pyridine (0.53 mL; 6.6 mmol) and 3,4-dichlorobenzoylchloride (0.69 g; 3.3 mmol). The reaction mixture was stirred for eight days and filtered. The resulting solid was washed with water, ethyl acetate and ethanol, then dried under vacuum to give Example 149a as a yellow solid.

Yield: 59% (0.75 g; 1.9 mmol).

¹H-NMR (DMSO-d₆) δ: 10.5 (s, 1H), 8.25 (broad s, 1H), 7.9 (broad d, 1H), 7.8 (broad d, 1H), 7.75 (broad d, 2H), 7.7 (broad s, 1H), 7.3 (broad m, 3H), 4.25 (d, 1H), 4.0 (d, 1H), 3.6 (d, 1H), 3.45 (d, 1H).

MS: 407 (M+Na).

III—Compounds Prepared According to Scheme D.

Examples 150 to 153 were synthesized according to Scheme D.

A—Preparation of Compound I

Example 150

Compound I wherein Ar is Ph, X is OCH₂, q is 0, substitution in ortho position, R² and R³ are H, Y—R¹ is CH₂COOMe.

A mixture of α,α′-dibromo-o-xylene (7.15 g, 27.1 mmol), methyl glycolate (2.87 g, 27.1 mmol) and K₂CO₃ (8.25 g, 59 mmol) in DMF (dry, 20 mL) was stirred under argon at room temperature for 4 h. Phenol (2.54 g, 27 mmol) was added to the reaction mixture and stirring was continued overnight. The reaction mixture was filtered and the residue was washed several times with EtOAc. Combined filtrate and washings were washed successively with 0.5N NaOH, water (twice) and brine, dried (magnesium sulfate), and concentrated to generate a crude product. It was purified by flash chromatography (eluent: hexane/ethyl acetate 85/15) to generate example 150 as a viscous oil.

Yield=18% (1.48 g; 4.9 mmol).

¹H-NMR (CDCl₃): δ 7.74-6.81 (a series of m, 9H), 5.20 (s, 2H), 3.96 (s, 2H), 3.66 (s, 3H), 3.31 (s, 2H).

MS: m/e 325 (M+Na).

Example 151

Compound I wherein Ar is Ph, X is OCH₂, q is 0, substitution in ortho position, R² and R³ are H, Y—R¹ is CH₂COOH.

A mixture of Example 150 (1.48 g, 4.9 mmol), 1N NaOH (25 mL) and methanol (25 mL) was kept under reflux for 4 h (the mixture became homogenous), cooled, concentrated, and diluted with water. It was then neutralized with conc. HCl. and extracted into ethyl acetate (twice). Combined organic layer was washed with water and brine, dried (MgSO₄) and concentrated to generate Example 151 as a viscous oil that was directly used in the next step.

Yield=88% (1.25 g; 4.34 mmol).

¹H-NMR (CDCl₃): δ 7.82-6.80 (a series of m, 9H), 5.20 (s, 2H), 3.98 (s, 2H), 3.14 (s, 2H).

Example 152

Compound I wherein Ar is Ph, X is OCH₂, q is 0, substitution in ortho position, R² and R³ are H, Y—R¹ is CH₂COONH₂.

A mixture of Example 151 (1.25 g, 4.34 mmol), HOBt.NH₃ complex (1.45 g, 9.53 mmol), TBTU (1.70 g, 5.29 mmol) in DMF (15 mL) was stirred at room temperature overnight. It was then diluted with dichloromethane and successively washed with water, 2% citric acid, water, 2% NaHCO₃, water and brine, dried (MgSO₄), and concentrated to generate a crude product. It was purified by flash chromatography (eluent: hexane/ethyl acetate 1/4) to generate Example 152.

Yield=67% (0.83 g; 2.89 mmol).

¹H-NMR (CDCl₃): δ 7.74-6.96 (a series of m, 9H), 6.52 (br s, 1H), 5.39 (br s, 1H), 5.16 (s, 2H), 3.89 (s, 2H), 3.14 (s, 2H).

Example 153 2-(2-Phenoxymethyl-phenylmethanesulfinyl)-acetamide

Compound I wherein Ar is Ph, X is OCH₂, q is 1, substitution in ortho position, R² and R³ are H, Y—R¹ is CH₂COONH₂.

To a solution of Example 152 (0.82 g, 2.87 mmol) in acetic acid (10 mL) was added hydrogen peroxide (50% in water, 200 μL). The reaction mixture was stirred at room temperature for 4 h, neutralized (carefully) with aq. NaHCO₃ solution and extracted into ethyl acetate (twice). Combined organic layer was washed with brine, dried (MgSO₄) and concentrated to give a crude product that was purified by flash chromatography (eluent dichloromethane/MeOH 93/7) to generate Example 153.

Yield=70% (0.61 g; 2.01 mmol).

m.p.: 153-154° C.

¹H-NMR (DMSO-d₆): δ 7.71 (s, 1H), 7.52 (s, 1H), 7.37-6.93 (a series of m, 9H), 5.21 (s, 2H), 4.39 (d, 1H), 4.17 (d, 1H), 3.77 (d, 1H), 3.55 (d, 1H).

MS: 326 (M+Na),

Biological Data

Methodology: Evaluation of Wake Promoting Activity in Rats

The methodology utilized for evaluating wake promoting activity of test compounds is based on that described by Edgar and Seidel, Journal of Pharmacology and Experimental Therapeutics, 283:757-769, 1997, and incorporated herein in its entirety by reference.

Animal Surgery. Adult, male Wistar rats (275-320 g from Charles River Laboratories, Wilmington, Mass.) were anesthetized (Nembutal, 45 mg/kg, ip.) and surgically prepared with implants for recording of chronic EEG (encephalographic) and EMG (electromyographic) recording. The EEG implants were made from commercially available components (Plastics One, Roanoke, Va.). EEG signals were recorded from stainless steel screw electrodes: 2 frontal (+3.0 mm AP from bregma, ±2.0 mm ML), and 2 occipital (−4.0 mm AP from bregma, ±2.0 mm ML). Two Teflon-coated stainless steel wires were positioned under the nuchal trapezoid muscles for EMG recording. All electrode leads were inserted into a connector pedestal and the pedestal affixed to the skull by application dental acrylic. Antibiotic was administered post surgically and antibiotic cream was applied to the wound edges to prevent infection. At least one week elapsed between surgery and recording.

Recording environment. Postsurgically, rats were housed in pairs in an isolated room. Food and water were available ad libitum, ambient temperature was 21° C., and humidity was 55%. At least 24 hrs prior to recording, they were placed in Nalgene containers (31×31×31 cm) with a wire-grid top, and entry to the room was prohibited during the day of recording except for dosing. The containers were placed on a rack with two shelves, 4 containers per shelf. Fluorescent overhead room lights were set to a 24 hr. light/dark cycle (on at 7 AM, off at 7 PM). Light levels inside the containers were 38 and 25 lux for the top and bottom shelves respectively. Background white-noise (68 db inside the containers) was present in the room to mask ambient sounds.

Data acquisition. EEG and EMG signals were led via cables to a commutator (Plastics One) and then to pre-amplifiers (model 1700, A-M Systems, Carlsborg, Wash.). EEG and EMG signals were amplified (10K and 1K respectively) and bandpass filtered between 0.3 and 500 Hz for EEG and between 10 and 500 Hz for EMG. These signals were digitized at 128 samples per second using ICELUS sleep research software (M. Opp, U. Texas; see Opp, Physiology and Behavior 63:67-74, 1998, and Imeri, Mancia, and Opp, Neuroscience 92:745-749, 1999, incorporated by reference herein in their entirety) running under Labview 5.1 software and data acquisition hardware (PCI-MIO-16E-4; National Instruments, Austin, Tex.). On the day of dosing, data was recorded for 6 to 10 hours beginning at 11 AM.

Drug administration and study design. Compounds were evaluated on groups of from 4 to 8 rats carried out over one or two separate test sessions. Each animal was tested with a different compound or vehicle for up to 10 weeks with at least 7 days between successive tests. A vehicle group was included in all experiments, and each animal received vehicle every 4^(th) test. Test compounds were suspended in sterile 0.25% methylcellulose (pH=6.2; Upjohn Co., Kalamazoo, Mich.) at 30 mg/mL. Although compounds can be administered at dosages greater than 100 mg/kg and are expected to be active under the selection criteria of data analysis, unless otherwise noted, compounds were administered at a single dose of 100 mg/kg. Dosing was carried out at noon, while the rats were predominantly asleep. Each rat was lifted out of its container, given an intraperitoneal injection in a volume of 5 mL/kg, and replaced. Dosing required approximately 30 sec per rat.

Sleep/wake scoring. Sleep and wake activity were determined manually using ICELUS software. This program displays the EEG and EMG data in blocks of 6 sec along with the EEG frequency spectrum. Arousal state was scored as awake, rapid eye-movement (REM), or slow-wave or non-REM sleep (NREM) according to visual analysis of EEG frequency and amplitude characteristics and EMG activity (Opp and Krueger, 1994; Van Gelder, et al., 1991; Edgar, et al., 1991, 1997; Seidel, et al, 1995, incorporated by reference herein in their entirety). Essentially, waking activity consists of relatively low-amplitude EEG activity with relatively lower power in the frequency band from 0.5-6 Hz, accompanied by moderate to high level EMG activity. In a particular waking state (“theta-waking”), EEG power can be relatively focused in the 6-9 Hz (theta) range, but significant EMG activity is always present. NREM sleep is characterized by relative high-amplitude EEG activity with relatively greater power in the low frequency band from 0.5-6 Hz, accompanied by little or no EMG activity. REM sleep is characterized by moderate and constant amplitude EEG focused in the theta (6-9 Hz) range, similar to waking theta, but with no EMG activity.

Data analysis and statistics. Two basic outcome measures were used to ascertain whether a compound exhibited wake-enhancing activity. The first was the percent time spent awake for each 30 min period following dosing. The second was the total time spent awake in the first 3 hrs following dosing (3 hr AUC; maximum 180 min). For purposes of ascertaining activity of a test compound, wake activity values were compared against corresponding vehicle values. The vehicle values were of two types. The first type was the corresponding within-experiment vehicle, that is, a value for the vehicle group run concurrently with the test compound. A second “reference” vehicle value consisted of the mean 3 hr AUC value calculated from 234 animals in 59 separate experiments carried out during the same time period as the evaluations of the test compounds (mean ±SD=69.22±20.12; 95% confidence limits=66.63-71.81). Two-tailed, unpaired t-tests were performed on the wake time values for drug versus vehicle treated animals, and compounds with p≦0.05 were deemed significantly wake-promoting. A test compound was considered “active” if it met one of the following three criteria.

-   -   (i). The 3 hr AUC value for the test compound was significantly         greater (p≦0.05) than the mean wake value for the reference         vehicle group (N=234).     -   (ii) The 3 hr AUC value for the test compound was significantly         greater (p≦0.05) than the corresponding value for the vehicle         group within the same experiment.     -   (iii) One or more of the half-hour wake time values from 0.5 to         2 hrs after dosing was significantly greater (p≦0.05) in the         test compound group than in the corresponding vehicle group         within the same experiment.

Results:

Compounds of the invention either have demonstrated or are expected to demonstrate utility for wake promoting activity.

As example, the three-hours AUC value (mean ±sem) for the reference vehicle group and for the test compounds are reported Table 9 for Examples 22, 40 and 113. These test compounds were administered by i.p. route at a 100 mg/kg dose and the time-course of the percent of time awake as function of time was estimated from 1 hr prior to 5 hours post dosing.

TABLE 9 Mean AUC_(0-3 h) values (±sem) for the reference vehicle group and for test compounds Test Vehicle compound Mean sem Mean sem p Example 22 67.1 5.3 162.7 6.5 0.000 Example 40 66.9 5.5 118.9 10.6 0.001 Example 113 63.5 9.1 99.0 10.4 0.022 AUC _(0-3 h) (% of waiking time × hr) − n = 8 Rats per test compound and 8 rats per control groups.

As compared to the control groups, compounds of Example 22, 40 and 113 produced a significantly greated wakefulness than that observed in the vehicle-treated animals (p<0.05).

REFERENCES

The following references, to the extent that they provide exemplary procedural or other details supplementary to those set forth herein, are specifically incorporated in their entirety herein by reference:

-   Touret, et al., Neuroscience Letters, 189:43-46, 1995. -   Van Gelder, R. N. et al., Sleep 14:48-55, 1991. -   Edgar, D. M., J. Pharmacol. Exp. Ther. 282:420-429, 1997. -   Edgar and Seidel, J. Pharmacol. Exp. Ther., 283:757-69, 1997. -   Hemant et al., Psychopharmacology, 103:28-32, 1991. -   Lin et al., Brain Research, 591:319-326, 1992. -   Opp and Krueger, American Journal of Physiology 266:R688-95, 1994 -   Panckeri et al., Sleep, 19(8):626-631, 1996. -   Seidel, W. F., et al., J. Pharmacol. Exp. Ther. 275:263-273, 1995. -   Shelton et al., Sleep 18(10):817-826, 1995. -   Welsh, D. K., et al., Physiol. Behav. 35:533-538, 1985.

Utility

The present invention provides a method of treating diseases and conditions in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a compound of formula (I). For example, the compounds of the present invention are use in the treatment of diseases, including treatment of sleepiness, promotion of wakefulness, treatment of Parkinson's disease, cerebral ischemia, stroke, sleep apneas, eating disorders, stimulation of appetite and weight gain, treatment of attention deficit hyperactivity disorder (“ADHD”), enhancing function in disorders associated with hypofunctionality of the cerebral cortex, including, but not limited to, depression, schizophrenia, fatigue, in particular, fatigue associated with neurologic disease, such as multiple sclerosis, chronic fatigue syndrome, and improvement of cognitive dysfunction.

Dosage and Formulation

The compounds of the present invention can be administered for therapeutic purposes by any means that results in the contact of the active agent with the agent's site of action in a subject. The compounds may be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination with other therapeutic agents, such as, for example, analgesics, or in combination with antidepressants, including but are not limited to tricyclic antidepressants (“TCAs”), Selective Serotonin Reuptake Inhibitors (“SSRIs”), Serotonin and Noradrenaline Reuptake Inhibitors (“SNRIs”), Dopamine Reuptake Inhibitors (“DRIs”), Noradrenaline Reuptake Inhibitors (“NRUs”), Dopamine, Serotonin and Noradrenaline Reuptake Inhibitors (“DSNRIs”) and Monoamine Oxidase Inhibitors (“MAOIs) including reversible inhibitors of monoamine oxidase type A (RIMAs). The compounds of the present invention are preferably administered in therapeutically effective amounts for the treatment of the diseases and disorders described herein.

A therapeutically effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of conventional techniques. The effective dose will vary depending upon a number of factors, including the pharmacodynamics of the active agent, the type and extent of progression of the disease or disorder, the age, weight and health of the particular patient, the formulation of the active and its mode and frequency of administration, and the desired effect with a minimization of side effects. Typically, the compounds are administered at lower dosage levels, with a gradual increase until the desired effect is achieved.

Typical dose ranges are from about 0.01 mg/kg to about 100 mg/kg of body weight per day, with a preferred dose from about 0.01 mg/kg to 10 mg/kg of body weight per day. A typical daily dose for adult humans can range from about 1 to about 1000 mg of the active agent, particularly from about 1 to about 400 mg, and including 25, 50, 85, 100, 150, 170, 200, 255, 250, 255, 340, 400, 425, 500, 600, 700, 750, 800, and 900 mg doses, and equivalent doses for a human child.

The compounds may be administered in one or more unit dose forms, and they may be administered in a single daily dose or in two, three or four doses per day. The unit dose ranges from about 1 to about 1000 mg, particularly from about 1 to about 400 mg, and including 25, 50, 85, 100, 150, 170, 200, 255, 250, 255, 340, 400, 425, 500, 600, 700, 750, 800, and 900 mg unit doses, and equivalent unit doses for a human child. In particular, the unit dosages range from about 1 to about 500 mg administered one to four times a day, preferably from about 10 mg to about 300 mg, two times a day. In an alternate method of describing an effective dose, an oral unit dose is one that is necessary to achieve a blood serum level of about 0.05 to 20 μg/ml in a subject, and preferably about 1 to 20 μg/ml.

The compounds of the present invention may be formulated into pharmaceutical compositions by admixture with one or more pharmaceutically acceptable excipients. The active agent may be present in about 0.5-95% by weight of the composition. The excipients are selected on the basis of the chosen route of administration and standard pharmaceutical practice, as described, for example, in Remington: The Science and Practice of Pharmacy, 20^(th) ed.; Gennaro, A. R., Ed.; Lippincott Williams & Wilkins: Philadelphia, Pa., 2000.

The compositions can be prepared for administration by oral means, including tablets, pills, powders, capsules, troches and the like; parenteral means, including intravenous, intramuscular, and subcutaneous means; topical or transdermal means, including patches, creams, ointments, lotions, pastes, gels, solutions, suspensions, aerosols, and powders and the like; transmucosal means, including nasal, rectal, vaginal, sublingual and buccal means; ophthalmic or inhalation means. Preferably the compositions are prepared for oral administration, particularly in the form of tablets, capsules or syrups; parenteral administration, particularly in the form of liquid solutions, suspensions or emulsions; intranasal administration, particularly in the form of powders, nasal drops, or aerosols; or for topical use, such as patches, creams, ointments, and lotions.

For oral administration, the tablets, pills, powders, capsules, troches and the like can contain one or more of the following: diluents or fillers such as starch, or cellulose; binders such as microcrystalline cellulose, gelatins, or polyvinylpyrrolidone; disintegrants such as starch or cellulose derivatives; lubricants such as talc or magnesium stearate; glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; and flavoring agents such as peppermint or cherry flavoring. Capsules may contain any of the above ingredients, and may also contain a semi-solid or liquid carrier, such as a polyethylene glycol. The solid oral dosage forms may have coatings of sugar, shellac, or enteric agents. Liquid preparations may be in the form of aqueous or oily suspensions, solutions, emulsions, syrups, elixirs, etc., or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as surfactants, suspending agents, emulsifying agents, diluents, sweetening and flavoring agents, dyes and preservatives.

The compositions may also be administered parenterally. The pharmaceutical forms acceptable for injectable use include, for example, sterile aqueous. solutions, or suspensions. Aqueous carriers include mixtures of alcohols and water, buffered media, and the like. Nonaqueous solvents include alcohols and glycols, such as ethanol, and polyethylene glycols; oils, such as vegetable oils; fatty acids and fatty acid esters, and the like. Other components can be added including surfactants; such as hydroxypropylcellulose; isotonic agents, such as sodium chloride; fluid and nutrient replenishers; electrolyte replenishers; agents which control the release of the active compounds, such as aluminum monostearate, and various co-polymers; antibacterial agents, such as chlorobutanol, or phenol; buffers; suspending agents; thickening agents; and the like. The parenteral preparations can be enclosed in ampules, disposable syringes or multiple dose vials. Other potentially useful parenteral delivery systems for the active compounds include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes.

Other possible modes of administration include formulations for inhalation, which include such means as dry powder, aerosol, or drops. They may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or oily solutions for administration in the form of nasal drops, or as a gel to be applied intranasally. Formulations for topical use are in the form of an ointment, cream, or gel. Typically these forms include a carrier, such as petrolatum, lanolin, stearyl alcohol, polyethylene glycols, or their combinations, and either an emulsifying agent, such as sodium lauryl sulfate, or a gelling agent, such as tragacanth. Formulations suitable for transdermal administration can be presented as discrete patches, as in a reservoir or microreservoir system, adhesive diffusion-controlled system or a matrix dispersion-type system. Formulations for buccal administration include, for example lozenges or pastilles and may also include a flavored base, such as sucrose or acacia, and other excipients such as glycocholate. Formulations suitable for rectal administration are preferably presented as unit-dose suppositories, with a solid based carrier, such as cocoa butter, and may include a salicylate.

The compositions of the present invention may be formulated to control and/or delay the release of the active agent(s). Such controlled-, delayed, sustained-, or extended-release compositions are well-known in the art, and may include, for example, reservoir or matrix diffusion products, as well as dissolution systems. Some compositions may utilize, for example biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers as excipients.

Preferred embodiments of the invention include the following:

1. A compound of formula (A):

wherein:

-   Ar is independently selected from C₆-C₁₀ aryl and 5 to 10-membered     heteroaryl wherein:     -   C₆-C₁₀ aryl and heteroaryl are optionally substituted with one         to three groups selected from F, Cl, Br, I, OR²², OR²⁵, NR²³R²⁴,         NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,         C₃-C₇ cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5 or 6         membered heteroaryl, arylalkyl, C(═O)R²², CO₂R²², OC(═O)R²²,         C(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²¹CO₂R²², OC(═O)NR²³R²⁴,         NR²¹C(═S)R²², and S(O)_(y)R²²; -   X is O, S(O)_(y), N(R¹⁰), OC(R²²)₂, (R²²)₂CO, C(R²²)₂NR²¹,     NR²¹C(R²²)₂, C(═O)NR²¹, NR²¹C(═O), S(O)—NR²², NR²²S(O)₂,     C(R²²)₂C(R²²)₂, CR²¹═CR²¹, C≡C; -   Y is C₁-C₆ alkylene; or     -   (C₁-C₄ alkylene)_(m)-Z-(C₁-C₄ alkylene)_(n);     -   wherein said alkylene groups are optionally substituted with one         to three R²⁰ groups; -   Z is O, NR^(10A), S(O)_(y), CR²¹═CR²¹, C≡C, C₆-C₁₀ arylene, 5-10     membered heteroarylene, C₃-C₆ cycloalkylene, or 3-6 membered     heterocycloalkylene; wherein said arylene, heteroarylene,     cycloalkylene, and heterocycloalkylene groups are optionally     substituted with one to three R²⁰ groups; -   R¹ is selected from NR¹²R¹³, NR²¹C(═O)R¹⁴, C(═O)R¹⁴, CO₂R¹¹,     OC(═O)R¹¹, C(═O)NR¹²R¹³, C(═NR¹¹)NR¹²R¹³, OC(═O)NR¹²R¹³,     NR²¹S(O)₂R¹¹, NR²¹C(═O)NR¹²R¹³, and NR²¹S(O)₂NR¹²R¹³;     -   wherein said aryl groups are optionally substituted with one to         three R²⁰ groups; -   R² and R³ are each independently selected from F, Cl, Br, I, OR²²,     OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆     alkynyl, C₃-C₇ cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5     or 6 membered heteroaryl, arylalkyl, C(═O)R²², CO₂R²², OC(═O)R²²,     C(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²¹CO₂R²², OC(═O)NR²³R²⁴, NR²¹C(═S)R²²,     and S(O)_(y)R²²; -   R¹⁰ and R^(10A) are each independently selected from H, C₁-C₆ alkyl,     C₆-C₁₀ aryl, C(═O)R¹⁴, and S(O)_(y)R¹⁴; wherein said alkyl and aryl     groups are optionally substituted with one to three R²⁰ groups; -   R¹¹ at each occurrence is independently selected from H, C₃-C₇ alkyl     and C₆-C₁₀ aryl;     -   wherein said alkyl and aryl group are optionally substituted         with one to three R²⁰ groups; -   R¹² and R¹³ at each occurrence are each independently selected from     H, C₁-C₆ alkyl, or R¹² and R¹³, together with the nitrogen to which     they are attached, form a 3-7 membered heterocyclic ring;     -   wherein said alkyl group and heterocyclic ring are optionally         substituted with one to three R²⁰ groups; -   R¹⁴ at each occurrence is independently selected from C₁-C₆ alkyl,     C₆-C₁₀ aryl, and arylalkyl;     -   wherein said alkyl, aryl and arylalkyl groups are optionally         substituted with one to three R²⁰ groups; -   R²⁰ at each occurrence is independently selected from F, Cl, Br, I,     OR²², OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl optionally     substituted by one to three OH, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇     cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5 or 6 membered     heteroaryl, arylalkyl, C(═O)R²², CO₂R²², OC(═O)R²², C(═O)NR²³R²⁴,     NR²¹C(═O)R²², NR²¹CO₂R²², OC(═O)NR²³R²⁴, NR²¹C(═S)R²², and     S(O)_(y)R²²; -   R²¹ at each occurrence is independently selected from H and C₁-C₆     alkyl; -   R²² at each occurrence is independently selected from H, C₁-C₆     alkyl, and C₆-C₁₀ aryl; -   R²³ and R²⁴ at each occurrence are each independently selected from     H, C₁-C₆ alkyl, and C₆-C₁₀ aryl, or R²³ and R²⁴, together with the     nitrogen to which they are attached, form a 3-7 membered     heterocyclic ring; -   R²⁵ at each occurrence is independently the residue of an amino acid     after the hydroxyl group of the carboxyl group is removed; -   m is 0 or 1; -   n is 0 or 1; -   q is 0, 1, or 2; -   y is 0, 1, or 2;     with the exclusion of the compounds wherein:     -   Y is C₂ alkylene substituted with one to three C₁-C₆ alkylene         and/or NR²³R²⁴ and/or NR²¹CO₂R²²; and     -   R¹ is C(═O)NR¹²R¹³.         and with the exclusion of the compound:     -   tetrahydro-2-[[{4-(phenylthio)phenyl]methyl}thio]acetyl]-2H-1,2-oxazine;         and the stereoisomeric forms, mixtures of stereoisomeric forms         or pharmaceutically acceptable salts forms thereof.

2. The compound according to claim 1, wherein:

-   Y is C₁-C₆ alkylene; -   (C₁-C₄ alkylene)_(m)-Z¹-(C₁-C₄ alkylene)_(n); -   C₁-C₄ alkylene-Z²-C₁-C₄ alkylene; -   wherein said alkylene groups are optionally substituted with one to     three R²⁰ groups; -   Z¹ is CR²¹═CR²¹, C≡C, C₆-C₁₀ arylene, 5-10 membered heteroarylene, -   C₃-C₆ cycloalkylene, or 3-6 membered heterocycloalkylene; wherein     said arylene, heteroarylene, cycloalkylene, and heterocycloalkylene     groups are optionally substituted with one to three R²⁰ groups; -   Z is O, NR^(10A), or S(O)_(y).

3. The compound according to any of claims 1 or 2 wherein q is 1.

4. The compound according to any of claims 1 to 3 wherein R¹ is H.

5. The compound according to any of claims 1 to 3 wherein R¹ is selected from NR¹²R¹³, NR²¹C(═O)R¹⁴, C(═O)R¹⁴, CO₂R¹¹, OC(═O)R¹¹, C(═O)NR¹²R¹³, C(═NR¹¹)NR¹²R¹³, OC(═O)NR¹²R¹³, NR²¹S(O)₂R¹¹, NR²¹C(═O)NR¹²R¹³, and NR²¹S(O)₂NR¹²R¹³.

6. The compound according to claim 5 wherein R¹ is selected from NR¹²R¹³; NR²¹C(═O)R¹⁴; C(═O)NR¹²R¹³; C(═NR¹¹)NR¹²R¹³; and NR²¹C(═O)NR¹²R¹³.

7. The compound according to claim 6 wherein R¹ is C(═O)NR¹²R¹³.

8. The compound according to any of the claims 5 to 7 wherein R¹² and R¹³ are each independently selected from H and C₁-C₆ alkyl.

9. The compound according to any of the claims 5 to 7 wherein R¹² and R¹³ together with the nitrogen to which they are attached, form a 3-7 membered heterocyclic ring, wherein said heterocyclic ring is optionally substituted with one R²⁰ group.

10. The compound according to claim 5 wherein R¹ is selected from C(═O)R¹⁴, CO₂R¹¹, OC(═O)R¹¹, C(═O)NR¹²R¹³, OC(═O)NR¹²R¹³, NR²¹S(O)₂R¹¹, and NR²¹S(O)₂NR¹²R¹³.

11. The compound according to claims 1 to 10 wherein X is O, S(O)_(y), N(R¹⁰).

12. The compound according to claims 1 to 10 wherein X is OC(R²²)₂, C(R²²)₂O, C(R²²)₂NR²¹, NR²¹C(R²²)₂, C(═O)N(R²¹), NR²¹C(═O), S(O)₂NR²², NR²²S(O)₂, C(R²²)₂C(R²²)₂.

13. The compound according to claim 12 wherein X is OC(R²²)₂, C(R²²)₂NR²¹, C(═O)N(R²¹), S(O)₂—NR²².

14. The compound according to any of claims 1 to 13 wherein Y is C₁-C₆ alkylene.

15. The compound according to claim 14 wherein Y is CH₂.

16. The compound according to any of claims 2 to 13 wherein Y is (C₁-C₄ alkylene)_(m)-Z¹—(C₁-C₄ alkylene)_(n).

17. The compound according to claim 16 wherein Z¹ is C₆-C₁₀ arylene or C₃-C₆ cycloalkylene.

18. The compound according to claim 17 wherein Z¹ is phenylene.

19. The compound according to claim 16 wherein Z¹ is 5-10 membered heteroarylene or 3-6 membered heterocycloalkylene.

20. The compound according to claim 16 wherein Z¹ is CR²¹═CR²¹ or C≡C.

21. The compound according to any of claims 2 to 13 wherein Y is C₁-C₄ alkylene-Z²—C₁-C₄ alkylene.

22. The compound according to claim 21 wherein Z² is O.

23. The compound according to claims 1 or 2 with the structure:

wherein:

-   Ar is independently selected from C₆-C₁₀ aryl and 5 to 10-membered     heteroaryl wherein:     -   C₆-C₁₀ aryl and heteroaryl are optionally substituted with one         to three groups selected from F, Cl, Br, I, OR²², OR²⁵, NR²³R²⁴,         NHOH, NO₂, CN, C₁-C₆ alkyl, phenyl, arylalkyl, and C(═O)R²²; -   X is O, S(O)_(y), N(R¹⁰), OC(R²²)₂, C(R²²)₂O, C(R²²)₂NR²¹,     NR²¹C(R²²)₂, C(═O)N(R²¹), NR²¹C(═O), S(O)₂NR²², NR²²S(O)₂; -   Y is C₁-C₆ alkylene;     -   C₁-C₄ alkylene-Z¹—(C₁-C₄ alkylene)_(n); or     -   C₁-C₄ alkylene-Z²—C₁-C₄ alkylene;     -   wherein said alkylene groups are optionally substituted with one         to three R²⁰ groups; -   Z¹ is CR²¹═CR²¹, C≡C, C₆-C₁₀ arylene, 5-10 membered heteroarylene,     C₃-C₆ cycloalkylene, or 3-6 membered heterocycloalkylene; -   Z² is O, NR^(10A), or S(O)_(y); -   R¹ is selected from NR²¹C(═O)R¹⁴, C(═O)R¹⁴, CO₂R¹¹, OC(═O)R¹¹,     C(═O)NR¹²R¹³, C(═NR¹¹)NR¹²R¹³, OC(═O)NR¹²R¹³, NR²¹S(O)₂R¹¹,     NR²¹C(═O)NR¹²R¹³, and NR²¹S(O)₂NR¹²R¹³; -   R² and R³ are each independently selected from F, Cl, Br, I, OR²²,     OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl, phenyl, 5 or 6     membered heteroaryl, arylalkyl, C(═O)R²²; -   R¹⁰ and R^(10A) are each independently selected from H, C₁-C₆ alkyl,     C(═O)R¹⁴, and S(O)_(y)R¹⁴;     -   wherein said alkyl groups are optionally substituted with one to         three R²⁰ groups; -   R¹¹ at each occurrence is independently selected from H or C₃-C₇     alkyl, wherein said alkyl group is optionally substituted with one     to three R²⁰ groups; -   R¹² and R¹³ at each occurrence are each independently selected from     H, and C₁-C₆ alkyl, or R¹² and R¹³, together with the nitrogen to     which they are attached, form a 3-7 membered heterocyclic ring;     -   wherein said alkyl group and heterocyclic ring are optionally         substituted with one to three R²⁰ groups; -   R¹⁴ at each occurrence is independently selected from C₁-C₆ alkyl,     C₆-C₁₀ aryl, and arylalkyl;     -   wherein said alkyl, aryl and arylalkyl groups are optionally         substituted with one to three R²⁰ groups; -   R²⁰ at each occurrence is independently selected from F, Cl, Br, I,     OR²², OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, phenyl, benzyl, C(═O)R²²,     CO₂R²², OC(═O)R²², C(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²¹CO₂R²²,     OC(═O)NR²³R²⁴, NR²¹C(═S)R²², and S(O)_(y)R²²; -   R²¹ at each occurrence is independently selected from H and C₁-C₆     alkyl; -   R²² at each occurrence is independently selected from H, C₁-C₆     alkyl, and C₆-C₁₀ aryl; -   R²³ and R²⁴ at each occurrence are each independently selected from     H, and C₁-C₆ alkyl, or R²³ and R²⁴ together with the nitrogen to     which they are attached, form a 3-7 membered heterocyclic ring; -   R²⁵ at each occurrence is independently the residue of an amino acid     after the hydroxyl group of the carboxyl group is removed; -   n is 0 or 1; -   y is 0, 1, or 2;     and the stereoisomeric forms, mixtures of stereoisomeric forms or     pharmaceutically acceptable salts forms thereof.

24. The compound according to claim 23 wherein:

-   Y is C₁-C₆ alkylene, C₁-C₄ alkylene-Z¹-C₁-C₄ alkylene, or C₁-C₄     alkylene-Z²-C₁-C₄ alkylene, wherein said alkylene groups are     optionally substituted with one to three C₁-C₆ alkyl groups;     -   Z¹ is CR²¹═CR²¹, C≡C, or phenyl;     -   Z² is O, NR^(10A), or S(O)_(y); -   X is O, S(O)_(y), N(R¹⁰), OC(R²²)₂, C(R²²)₂O, C(R²²)₂NR²¹,     NR²¹C(R²²)₂, C(═O)N(R²¹), NR²¹C(═O), S(O)₂NR²², NR²²S(O)₂; and -   R¹ is selected from NR²¹C(═O)R¹⁴, C(═O)R¹⁴, CO₂R¹¹, OC(═O)R¹¹, and     C(═O)NR¹²R¹³.

25. The compound according to claim 24 wherein R¹ is C(═O)NR¹²R¹³.

26. The compound according to claim 25 having the structure of formula (Ib):

27. The compound according to claim 26 wherein X is O, S(O)_(y), N(R¹⁰), OC(R²²)₂, C(R²²)₂O, C(R²²)₂NR²¹, NR²¹C(R²²)₂, C(═O)N(R²¹), NR²¹C(═O), S(O)₂—NR²², NR²²S(O)₂.

28. The compound according to claim 27 wherein X is O, S(O)_(y), NH.

29. The compound according to claim 27 wherein X is OCH₂, CH₂O, CH₂NH, NHCH₂, C(═O)NH, NHC(═O), S(O)₂NH, NHS(O)₂.

30. The compound according to any of claims 27 wherein X is NH, O—CH₂, CH₂NH, C(═O)NH, S(O)₂—NH.

31. The compound according to any of claims 1 to 30 wherein R² and R³ are each independently selected from F, Cl, Br, I, OR²², OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl, phenyl, 5 or 6 membered heteroaryl, arylalkyl, C(═O)R²².

32. The compound according to any of claims 26 to 31 wherein Y is C₁-C₆ alkylene.

33. The compound according to claim 32 wherein Y is CH₂.

34. The compound according to any of claims 26 to 31 wherein Y is (C₁-C₄ alkylene)_(n)-Z¹—C₁-C₄ alkylene and Z¹ is phenyl, 5-6 membered heteroarylene, CR²¹═CR²¹, or C≡C.

35. The compound according to claim 1 selected in accordance with the following table, wherein:

TABLE 1

Ex. n° Ar X Position* R² R³ q Y—R¹ 13 3,4-DiClPh O para H H 0 CH₂CO—N-piperazinyl-N-Boc 14 3,4-DiClPh O para H H 0 CH₂CO—N-piperazinyl 19 3,4-DiClPh O para H H 1 CH₂CO—N-piperazinyl 16 4-ClPh S para H H 0 CH₂CO-1-(4-acetyl)-piperazinyl 23 4-ClPh S para H H 1 CH₂CO-1-(4-acetyl)-piperazinyl 24 4-ClPh SO para H H 1 CH₂CO-1-(4-acetyl)-piperazinyl 29 Ph O para H H 1 CH₂CONHCHMe₂ Ph O meta H H 0 CH₂CO—N-pyrrolidinyl 31 Ph O meta H H 1 CH₂CO—N-pyrrolidinyl Ph O meta H H 0 CH₂CONH₂ 32 Ph O meta H H 1 CH₂CONH₂ Ph O meta H H 0 CH₂CONMe₂ 33 Ph O meta H H 1 CH₂CONMe₂ Ph O meta H H 0 CH₂CONHCHMe₂ 34 Ph O meta H H 1 CH₂CONHCHMe₂ Ph O meta H H 0 CH₂CO-1-(4-acetyl)-piperazinyl 35 Ph O meta H H 1 CH₂CO-1-(4-acetyl)-piperazinyl 4-OCH₃Ph O para H H 0 CH₂CONH₂ 36 4-OCH₃Ph O para H H 1 CH₂CONH₂ 4-OCH₃Ph O para H H 0 CH₂CO-1-(4-acetyl)-piperazinyl 37 4-OCH₃Ph O para H H 1 CH₂CO-1-(4-acetyl)-piperazinyl 4-OCH₃Ph O para H H 0 CH₂CO—N-piperazinyl 38 4-OCH₃Ph O para H H 1 CH₂CO—N-piperazinyl 3,4-DiClPh O para H H 0 CH₂CONH₂ 39 3,4-DiClPh O para H H 1 CH₂CONH₂ 11 3,4-DiClPh O para H H 0 CH₂CO-1-(4-acetyl)-piperazinyl 22 3,4-DiClPh O para H H 1 CH₂CO-1-(4-acetyl)-piperazinyl 27 3,4-DiClPh O para H H 2 CH₂CO-1-(4-acetyl)-piperazinyl 30 3,4-DiClPh O para H H 1 CH₂COOH 15 3,4-DiClPh O ortho H H 0 CH₂CONH₂ 20 3,4-DiClPh O ortho H H 1 CH₂CONH₂ 3,4-DiClPh O ortho H H 0 CH₂CO-1-(4-acetyl)-piperazinyl 40 3,4-DiClPh O ortho H H 1 CH₂CO-1-(4-acetyl)-piperazinyl 3,4-DiClPh O para H H 0 CH₂CO-1-(4-carboxamide)-piperazinyl 41 3,4-DiClPh O para H H 1 CH₂CO-1-(4-carboxamide)-piperazinyl 4-OCH₃Ph O ortho H H 0 CH₂CONH₂ 42 4-OCH₃Ph O ortho H H 1 CH₂CONH₂ 2-ClPh O para H H 0 CH₂CONH₂ 43 2-ClPh O para H H 1 CH₂CONH₂ 4-OHPh O ortho H H 0 CH₂CONH₂ 44 4-OHPh O ortho H H 1 CH₂CONH₂ 2-ClPh O ortho H H 0 CH₂CONH₂ 45 2-ClPh O ortho H H 1 CH₂CONH₂ 2-ClPh O para H H 0 CH₂CO-1-(4-acetyl)-piperazinyl 46 2-ClPh O para H H 1 CH₂CO-1-(4-acetyl)-piperazinyl 2-ClPh O para H H 0 CH₂CO—N-piperazinyl 47 2-ClPh O para H H 1 CH₂CO—N-piperazinyl 4-FPh O para H H 0 CH₂CO-1-(4-acetyl)-piperazinyl 48 4-FPh O para H H 1 CH₂CO-1-(4-acetyl)-piperazinyl 95 4-FPh O para H H 2 CH₂CO-1-(4-acetyl)-piperazinyl 96 4-FPh O para H H 1 CH₂COOH 4-FPh O ortho H H 0 CH₂CO-1-(4-acetyl)-piperazinyl 49 4-FPh O ortho H H 1 CH₂CO-1-(4-acetyl)-piperazinyl 4-FPh O para H H 0 CH₂CONH₂ 50 4-FPh O para H H 1 CH₂CONH₂ 4-FPh O ortho H H 0 CH₂CONH₂ 51 4-FPh O ortho H H 1 CH₂CONH₂ 2-Naphthyl O ortho H H 0 CH₂CONH₂ 52 2-Naphthyl O ortho H H 1 CH₂CONH₂ 2-Naphthyl O ortho H H 0 CH₂CO-1-(4-acetyl)-piperazinyl 53 2-Naphthyl O ortho H H 1 CH₂CO-1-(4-acetyl)-piperazinyl 2-Naphthyl O para H H 0 CH₂CONH₂ 54 2-Naphthyl O para H H 1 CH₂CONH₂ 2-BiPh O para H H 0 CH₂CONH₂ 55 2-BiPh O para H H 1 CH₂CONH₂ 2-BiPh O ortho H H 0 CH₂CONH₂ 56 2-BiPh O ortho H H 1 CH₂CONH₂ 2-ClPh O ortho H H 0 CH₂CO-1-(4-acetyl)-piperazinyl 57 2-ClPh O ortho H H 1 CH₂CO-1-(4-acetyl)-piperazinyl 2-Naphthyl O para H H 0 CH₂CO-1-(4-acetyl)-piperazinyl 58 2-Naphthyl O para H H 1 CH₂CO-1-(4-acetyl)-piperazinyl 2-BiPh O ortho H H 0 CH₂CO-1-(4-acetyl)-piperazinyl 59 2-BiPh O ortho H H 1 CH₂CO-1-(4-acetyl)-piperazinyl 2-BiPh O para H H 0 CH₂CO-1-(4-acetyl)-piperazinyl 60 2-BiPh O para H H 1 CH₂CO-1-(4-acetyl)-piperazinyl 4-ClPh O para H H 0 CH₂CO-1-(4-acetyl)-piperazinyl 61 4-ClPh O para H H 1 CH₂CO-1-(4-acetyl)-piperazinyl 4-OCH₃Ph O para H H 0 CH₂CO-1-(4-methyl)-piperazinyl 62 4-OCH₃Ph O para H H 1 CH₂CO-1-(4-methyl)-piperazinyl 3,4-DiClPh O para H H 0 CH₂CO-l-(4-ethylcarboxylate)-piperazinyl 63 3,4-DiClPh O para H H 1 CH₂CO-1-(4-ethylcarboxylate)-HHpiperazinyl 4-FPh O para H H 0 CH₂CO-1-(4-hydroxyethyl)-piperazinyl 64 4-FPh O para H H 1 CH₂CO-1-(4-hydroxyethyl)-piperazinyl 3,4-DiClPh O ortho H H 0 CH₂CO-1-(4-hydroxyethyl)-piperazinyl 65 3,4-DiClPh O ortho H H 1 CH₂CO-1-(4-hydroxyethyl)-piperazinyl 4-FPh O para H H 0 CH₂CO-1-(4-methyl)-piperazinyl 66 4-FPh O para H H 1 CH₂CO-1-(4-methyl)-piperazinyl 4-ClPh O para H H 0 CH₂CONH₂ 67 4-ClPh O para H H 1 CH₂CONH₂ 4-FPh O para H H 0 CH₂CO-1-(4-ethylcarboxylate)-piperazinyl 68 4-FPh O para H H 1 CH₂CO-1-(4-ethylcarboxylate)-piperazinyl 4-OCH₃Ph O para H H O CH₂CO-1-(4-ethylcarboxylate)-piperazinyl 69 4-OCH₃Ph O para H H 1 CH₂CO-1-(4-ethylcarboxylate)-piperazinyl 4-ClPh S para H H 0 CH₂CO-1-(4-ethylcarboxylate)-piperazinyl 70 4-ClPh S para H H 1 CH₂CO-1-(4-ethylcarboxylate)-piperazinyl 71 4-ClPh SO para H H 1 CH₂CO-1-(4-ethylcarboxylate)-piperazinyl 3,4-DiClPh O ortho H H 0 CH₂CO-1-(4-ethylcarboxylate)-piperazinyl 72 3,4-DiClPh O ortho H H 1 CH₂CO-1-(4-ethylcarboxylate)-piperazinyl Ph O ortho H H 0 CH₂CONH₂ 97 Ph O ortho H H 1 CH₂CONH₂ Ph O ortho H H 0 CH₂CO—N-pyrrolidinyl 98 Ph O ortho H H 1 CH₂CO—N-pyrrolidinyl Ph O ortho H H 0 CH₂CONMe₂ 99 Ph O ortho H H 1 CH₂CONMe₂ Ph O para H H 0 CH₂CONMe₂ 100 Ph O para H H 1 CH₂CONMe₂ Ph O para H H 0 CH₂CO—N-pyrrolidinyl 101 Ph O para H H 1 CH₂CO—N-pyrrolidinyl Ph O para H H 0 CH₂CONH₂ 102 Ph O para H H 1 CH₂CONH₂ Ph O ortho H H 0 CH₂CONHCH₂CN 103 Ph O ortho H H 1 CH₂CONHCH₂CN Ph O ortho H H 0 CH₂CONHCHMe₂ 104 Ph O ortho H H 1 CH₂CONHCHMe₂ Ph O ortho H H 0 CH₂CONHCMe₃ 105 Ph O ortho H H 1 CH₂CONHCMe₃ Ph O ortho H H 0 CH₂CO-1-(4-hydroxy)-piperidinyl 106 Ph O ortho H H 1 CH₂CO-1-(4-hydroxy)-piperidinyl 12 Ph O ortho H H 0 CH₂CONH(CH₂)₂OH 21 Ph O ortho H H 1 CH₂CONH(CH₂)₂OH Ph O ortho H H 0 CH₂CO-1-(4-acetyl)-piperazinyl 107 Ph O ortho H H 1 CH₂CO-1-(4-acetyl)-piperazinyl Ph O meta H H 0 CH₂CONH(CH₂)₂OH 108 Ph O meta H H 1 CH₂CONH(CH₂)₂OH Ph O meta H H 0 CH₂CO-1-(4-hydroxy)-piperidinyl 109 Ph O meta H H 1 CH₂CO-1-(4-hydroxy)-piperidinyl 110 Ph O para H H 1 CH₂CO-1-(4-acetyl)-piperazinyl 111 Ph O para H H 1 CH₂CONH(CH₂)₂OH 112 Ph O para H H 1 CH₂CO-1-(4-hydroxy)-piperazinyl 113 4-ClPh CONH ortho H H 1 CH₂CONH₂ 114 3,4-DiOCH₃Ph CONH ortho H H 1 CH₂CONH₂ 115 2-Naphthyl CONH ortho H H 1 CH₂CONH₂ 116 4-ClPh CONH ortho H H 1 CH₂CO-1-(4-acetyl)-piperazinyl 117 3,4DiFPh CONH ortho H H 1 CH₂CONH₂ 118 2,4-DiOCH₃Ph CONH ortho H H 1 CH₂CONH₂ 119 3,4,5-TriOCH₃Ph CONH ortho H H 1 CH₂CONH₂ 120 3,4-DiOCH₃Ph CONH meta H H 1 CH₂CONH₂ 121 2,4-DiOCH₃Ph CONH ortho H H 1 CH₂CO-1-(4-acetyl)-piperazinyl 122 3,4-DiOCH₃Ph CONH ortho H H 1 CH₂CO-1-(4-acetyl)-piperazinyl 123 4-FPh CONH ortho H H 1 CH₂CO-1-(4-acetyl)-piperazinyl 124 3,4-DiClPh CONH ortho H H 1 CH₂CO-1-(4-acetyl)-piperazinyl 125 2,4-DiOCH₃Ph CONH meta H H 1 CH₂CONH₂ 126 4-FPh CONH meta H H 1 CH₂CONH₂ 127 3,4-DiClPh CONH meta H H 1 CH₂CONH₂ 4-ClPh S ortho H H 0 CH₂CO—N-piperazinyl 73 4-ClPh S ortho H H 1 CH₂CO—N-piperazinyl 2,3-DiClPh O ortho H H 0 CH₂CO-1-(4-acetyl)-piperazinyl 74 2,3-DiClPh O ortho H H 1 CH₂CO-1-(4-acetyl)-piperazinyl 2,5-DiClPh O ortho H H 0 CH₂CO-1-(4-acetyl)-piperazinyl 75 2,5-DiClPh O ortho H H 1 CH₂CO-1-(4-acetyl)-piperazinyl 2,5-DiClPh O ortho H H 0 CH₂CONH₂ 76 2,5-DiClPh O ortho H H 1 CH₂CONH₂ 2,3-DiClPh O ortho H H 0 CH₂CONH₂ 77 2,3-DiClPh O ortho H H 1 CH₂CONH₂ 2,4-DiClPh O para H H 0 CH₂CO-1-(4-acetyl)-piperazinyl 78 2,4-DiClPh O para H H 1 CH₂CO-1-(4-acetyl)-piperazinyl 2,4-DiClPh O ortho H H 0 CH₂CO-1-(4-acetyl)-piperazinyl 79 2,4-DiClPh O ortho H H 1 CH₂CO-1-(4-acetyl)-piperazinyl 2,4-DiClPh O para H H 0 CH₂CONH₂ 80 2,4-DiClPh O para H H 1 CH₂CONH₂ 2,4-DiClPh O ortho H H 0 CH₂CONH₂ 81 2,4-DiClPh O ortho H H 1 CH₂CONH₂ 3,5-DiClPh O ortho H H 0 CH₂CO-1-(4-acetyl)-piperazinyl 82 3,5-DiClPh O ortho H H 1 CH₂CO-1-(4-acetyl)-piperazinyl 3,5-DiClPh O para H H 0 CH₂CO-1-(4-acetyl)-piperazinyl 83 3,5-DiClPh O para H H 1 CH₂CO-1-(4-acetyl)-piperazinyl 3,5-DiClPh O para H H 0 CH₂CONH₂ 84 3,5-DiClPh O para H H 1 CH₂CONH₂ 3,5-DiClPh O ortho H H 0 CH₂CONH₂ 85 3,5-DiClPh O ortho H H 1 CH₂CONH₂ 2,5-DiClPh O para H H 0 CH₂CO-1-(4-acetyl)-piperazinyl 86 2,5-DiClPh O para H H 1 CH₂CO-1-(4-acetyl)-piperazinyl 3,4-DiClPh S para H H 0 CH₂CO-1-(4-acetyl)-piperazinyl 87 3,4-DiClPh S para H H 1 CH₂CO-1-(4-acetyl)-piperazinyl 2,5-DiClPh S para H H 0 CH₂CONH₂ 88 2,5-DiClPh S para H H 1 CH₂CONH₂ 3,4-DiClPh S para H H 0 CH₂CONH₂ 89 3,4-DiClPh S para H H 1 CH₂CONH₂ 2,3-DiClPh O para H H 0 CH₂CO-1-(4-acetyl)-piperazinyl 90 2,3-DiClPh O para H H 1 CH₂CO-1-(4-acetyl)-piperazinyl 2,6-DiClPh O para H H 0 CH₂CO-1-(4-acetyl)-piperazinyl 91 2,6-DiClPh O para H H 1 CH₂CO-1-(4-acetyl)-piperazinyl 2,6-DiClPh O para H H 0 CH₂CONH₂ 92 2,6-DiClPh O para H H 1 CH₂CONH₂ 2,3-DiClPh O para H H 0 CH₂CONH₂ 93 2,3-DiClPh O para H H 1 CH₂CONH₂ 94 2,3-DiClPh O para H H 2 CH₂CONH₂ 135 Ph NH ortho H H 1 CH₂CO-1-(4-acetyl)-piperazinyl 136 Ph NH para H H 1 CH₂CO-1-(4-acetyl)-piperazinyl 134 4-OCH₃Ph NH ortho H H 1 CH₂CO-1-(4-acetyl)-piperazinyl 131 4-FPh SO₂NH para H H 1 CH₂CO-1-(4-acetyl)-piperazinyl 137 4-OCH₃Ph NH para H H 1 CH₂CO-1-(4-acetyl)-piperazinyl 138 4-FPh NH para H H 1 CH₂CO-1-(4-acetyl)-piperazinyl 139 4-ClPh NH para H H 1 CH₂CO-1-(4-acetyl)-piperazinyl 140 4-FPh NH para H H 1 CH₂CO-1-(4-acetyl)-piperazinyl 128 3,4-DiClPh CONH para H H 1 CH₂CO-1-(4-acetyl)-piperazinyl 129 4-FPh CONH para H H 1 CH₂CO-1-(4-acetyl)-piperazinyl 141 3,4-DiClPh NH para H H 1 CH₂CO-1-(4-acetyl)-piperazinyl 132 4-ClPh SO₂NH para H H 1 CH₂CO-1-(4-acetyl)-piperazinyl 147 4-FPh CH₂NH para H H 1 CH₂CO-1-(4-acetyl)-piperazinyl 133 3,4-DiClPh SO₂NH para H H 1 CH₂CO-1-(4-acetyl)-piperazinyl 148 3,4-DiClPh CH₂NH para H H 1 CH₂CO-1-(4-acetyl)-piperazinyl 149 4-FPh CH₂NH ortho H H 1 CH₂CO-1-(4-acetyl)-piperazinyl 146 3,4-DiClPh CH₂NH ortho H H 1 CH₂CO-1-(4-acetyl)-piperazinyl 130 3,4-DiClPh SO₂NH ortho H H 1 CH₂CO-1-(4-acetyl)-piperazinyl 145 2-Furyl CH₂NH ortho H H 1 CH₂CO-1-(4-acetyl)-piperazinyl 144 2-Thienyl CH₂NH ortho H H 1 CH₂CO-1-(4-acetyl)-piperazinyl 142 2-Thienyl CONH ortho H H 1 CH₂CO-1-(4-acetyl)-piperazinyl 143 2-Furyl CONH ortho H H 1 CH₂CO-1-(4-acetyl)-piperazinyl 152 Ph OCH₂ ortho H H 0 CH₂CONH₂ 153 Ph OCH₂ ortho H H 1 CH₂CONH₂ 17 4-ClPh O para 2′-Cl H 0 CH₂CO-1-(4-acetyl)-piperazinyl 18 4-ClPh O para 2′-Cl H 0 CH₂CONH2 25 4-ClPh O para 2′-Cl H 1 CH₂CO-1-(4-acetyl)-piperazinyl 26 4-ClPh O para 2′-Cl H 1 CH₂CONH₂ 149a 3,4-DiClPh CONH para H H 1 CH₂CONH₂ 109a 4-ClPh O ortho H H 1 CH₂CONH₂ 109b 3-Cl-4-FPh O ortho H H 1 CH₂CONH₂ 109c 4-Cl-3-FPh O ortho H H 1 CH₂CONH₂ 109d 3-Cl-4-FPh O ortho H H 2 CH₂CONH₂  10a 4-ClPh O ortho 4′-Cl H 0 CH₂COOH  18a 4-ClPh O ortho 4′-Cl H 0 CH₂CONH₂  27a 4-ClPh O ortho 4′-Cl H 1 CH₂CONH₂  27b 4-ClPh O ortho 4′-Cl H 2 CH₂CONH₂ 109e 3,4-DiFPh O ortho 4′-Cl H 1 CH₂CONH₂ 109f 3,4-DiClPh O ortho H H 2 CH₂CONH₂  30a 3,4-DiClPh O ortho H H 1 CH₂COOH  30d 3,4-DiClPh O ortho H H 0 CH₂COOMenthyl (1R, 2S, 5R)  30e 3,4-DiClPh O ortho H H 1 CH₂COOH (−)  30f 3,4-DiClPh O ortho H H 1 CH₂COOH (+)  20a 3,4-DiClPh O ortho H H 1 CH₂CONH₂ (−)  20b 3,4-DiClPh O ortho H H 1 CH₂CONH₂ (+)  30b 3,4-DiClPh O ortho H H 2 CH₂COOH 112a 3,4-DiClPh O ortho H H 1 CH₂CONHCH₃ 112b 3,4-DiClPh O ortho H H 1 CH₂CON(C₂H₅)₂  30f 3,4-DiClPh O ortho H H 0 CH₂CON(CH₃)₂  30g 3,4-DiClPh O ortho H H 1 CH₂CON(CH₃)₂ Ph = phenyl, ClPh = chlorophenyl, DiClPh = di-chlorophenyl, FPh = Fluoprophenyl. *Position: the position refers to the position of the ArX lateral side chain as compared to —CH₂—S(O)_(q)—Y—R¹ group on the central benzyl ring. Ortho is position 2′, meta is position 3′ and para is position 4′.

36. A use of a compound of formula (A)

wherein:

-   Ar is independently selected from C₆-C₁₀ aryl and 5 to 10-membered     heteroaryl wherein:     -   C₆-C₁₀ aryl and heteroaryl are optionally substituted with one         to three groups selected from F, Cl, Br, I, OR²², NR²³R²⁴, NHOH,         NO₂, CN, CF₃, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇         cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5 or 6         membered heteroaryl, arylalkyl, C(═O)R²², CO₂R²², OC(═O)R²²,         C(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²¹CO₂R²², OC(═O)NR²³R²⁴,         NR²¹C(═S)R²², and S(O)_(y)R²²; -   X is O, S(O)_(y), N(R¹⁰) OC(R²²)₂, (R²²)₂C—O, C(R²²)₂NR²¹,     NR²¹C(R²²)₂, C(═O)N(R²¹), NR²¹C(═O), S(O)₂—NR²², NR²²S(O)₂,     C(R²²)₂C(R²²)₂, CR²¹═CR²¹, C≡C; -   Y is C₁-C₆alkylene; or     -   (C₁-C₄ alkylene)_(m)-Z-(C₁-C₄ alkylene)_(n);     -   wherein said alkylene groups are optionally substituted with one         to three R²⁰ groups; -   Z is O, NR^(10A), S(O)_(y), CR²¹═CR²¹, C≡C, C₆-C₁₀arylene, 5-10     membered heteroarylene, C₃-C₆ cycloalkylene, or 3-6 membered     heterocyclo-alkylene; wherein said arylene, heteroarylene,     cycloalkylene, and heterocycloalkylene groups are optionally     substituted with one to three R²⁰ groups; -   R¹ is selected from C₆-C₁₀ aryl, NR¹²R¹³, NR²¹C(═O)R¹⁴, C(═O)R¹⁴,     CO₂R¹¹, OC(═O)R¹¹, C(═O)NR¹²R¹³, C(═NR¹¹)NR¹²R¹³, OC(═O)NR¹²R¹³,     NR²¹S(O)₂R¹¹, NR²¹C(═O)NR¹²R¹³, and NR²¹S(O)₂NR¹²R¹³;     -   wherein said aryl groups are optionally substituted with one to         three R²⁰ groups; -   R² and R³ are each independently selected from F, Cl, Br, I, OR²²,     OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆     alkynyl, C₃-C₇ cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5     or 6 membered heteroaryl, arylalkyl, C(═O)R²², CO₂R²², OC(═O)R²²,     C(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²¹CO₂R²², OC(═O)NR²³R²⁴, NR²¹C(═S)R²²,     and S(O)_(y)R²²; -   R¹⁰ and R^(10A) are each independently selected from H, C₁-C₆ alkyl,     C₆-C₁₀ aryl, C(═O)R¹⁴, and S(O)_(y)R¹⁴; wherein said alkyl and aryl     groups are optionally substituted with one to three R²⁰ groups; -   R¹¹ at each occurrence is independently selected from H, C₁-C₆     alkyl, and C₆-C₁₀ aryl; wherein said alkyl and aryl groups are     optionally substituted with one to three R²⁰ groups; -   R¹² and R¹³ at each occurrence are each independently selected from     H, C₁-C₆ alkyl, and C₆-C₁₀ aryl, or R¹² and R¹³, together with the     nitrogen to which they are attached, form a 3-7 membered     heterocyclic ring;     -   wherein said alkyl and aryl groups and heterocyclic ring are         optionally substituted with one to three R²⁰ groups; -   R¹⁴ at each occurrence is independently selected from C₁-C₆ alkyl,     C₆-C₁₀ aryl, and arylalkyl;     -   wherein said alkyl, aryl and arylalkyl groups are optionally         substituted with one to three R²⁰ groups; -   R²⁰ at each occurrence is independently selected from F, Cl, Br, I,     OR²², OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl optionally     substituted by one to three OH, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇     cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5 or 6 membered     heteroaryl, arylalkyl, C(═O)R²², CO₂R²², OC(═O)R²², C(═O)NR²³R²⁴,     NR²¹C(═O)R²², NR²¹CO₂R²², OC(═O)NR²³R²⁴, NR²¹C(═S)R²², and     S(O)_(y)R²²; -   R²¹ at each occurrence is independently selected from H and C₁-C₆     alkyl; -   R²² at each occurrence is independently selected from H, C₁-C₆     alkyl, and C₆-C₁₀ aryl; -   R²³ and R²⁴ at each occurrence are each independently selected from     H, C₁-C₆ alkyl, and C₆-C₁₀ aryl, or R²³ and R²⁴, together with the     nitrogen to which they are attached, form a 3-7 membered     heterocyclic ring; -   R²⁵ at each occurrence is independently the residue of an amino acid     after the hydroxyl group of the carboxyl group is removed; -   m is 0 or 1; -   n is 0 or 1; -   q is 0, 1, or 2; -   y is 0, 1, or 2;     and the stereoisomeric forms, mixtures of stereoisomeric forms or     pharmaceutically acceptable salts forms thereof,     for the manufacture of a medicament useful for treating a disease or     a disorder selected from the group consisting of sleepiness     associated with narcolepsy, obstructive sleep apnea or shift work     disorder; Parkinson's disease; Alzheimer's disease; attention     deficit disorder; attention deficit hyperactivity disorder;     depression; and fatigue.

37. The use according to claim 36 for the manufacture of a medicament useful for the treatment of sleepiness associated with narcolepsy.

38. A use of a compound of formula (A)

wherein:

-   Ar is independently selected from C₆-C₁₀ aryl and 5 to 10-membered     heteroaryl wherein:     -   C₆-C₁₀ aryl and heteroaryl are optionally substituted with one         to three groups selected from F, Cl, Br, I, OR²², OR²⁵, NR²³R²⁴,         NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,         C₃-C₇ cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5 or 6         membered heteroaryl, arylalkyl, C(═O)R²², CO₂R²², OC(═O)R²²,         C(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²¹CO₂R²², OC(═O)NR²³R²⁴,         NR²¹C(═S)R²², and S(O)_(y)R²²; -   X is O, S(O)_(y), N(R¹⁰), OC(R²²)₂, (R²²)₂C—O, C(R²²)₂NR²¹,     NR²¹C(R²²)₂, C(═O)N(R²¹), NR²¹C(═O), S(O)₂—NR²², NR²²S(O)₂,     C(R²²)₂C(R²²)₂, CR²¹═CR²¹, C≡C; -   Y is C₁-C₆ alkylene; or     -   (C₁-C₄ alkylene)_(m)-Z-(C₁-C₄ alkylene)_(n);     -   wherein said alkylene groups are optionally substituted with one         to three R²⁰ groups; -   Z is O, NR^(10A), S(O)_(y), CR²¹═CR²¹, C≡C, C₆-C₁₀arylene, 5-10     membered heteroarylene, C₃-C₆ cycloalkylene, or 3-6 membered     heterocyclo-alkylene; wherein said arylene, heteroarylene,     cycloalkylene, and heterocycloalkylene groups are optionally     substituted with one to three R²⁰ groups; -   R¹ is selected from C₆-C₁₀ aryl, NR¹²R¹³, NR²¹C(═O)R¹¹, C(═O)R¹⁴,     CO₂R¹¹, OC(═O)R¹¹, C(═O)NR¹²R¹³, C(═NR¹¹)NR¹²R¹³, OC(═O)NR¹²R¹³,     NR²¹S(O)₂R¹¹, NR²¹C(═O)NR¹²R¹³, and NR²¹S(O)₂NR¹²R¹³;     -   wherein said aryl groups are optionally substituted with one to         three R²⁰ groups; -   R² and R³ are each independently selected from F, Cl, Br, I, OR²²,     OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆     alkynyl, C₃-C₇ cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5     or 6 membered heteroaryl, arylalkyl, C(═O)R²², CO₂R²², OC(═O)R²²,     C(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²¹CO₂R²², OC(═O)NR²³R²⁴, NR²¹C(═S)R²²,     and S(O)_(y)R²²; -   R¹⁰ and R^(10A) are each independently selected from H, C₁-C₆ alkyl,     C₆-C₁₀ aryl, C(═O)R¹⁴, and S(O)_(y)R¹⁴; wherein said alkyl and aryl     groups are optionally substituted with one to three R²⁰ groups; -   R¹¹ at each occurrence is independently selected from H, C₁-C₆     alkyl, and C₆-C₁₀ aryl; wherein said alkyl and aryl groups are     optionally substituted with one to three R²⁰ groups; -   R¹² and R¹³ at each occurrence are each independently selected from     H, C₁-C₆ alkyl, and C₆-C₁₀ aryl, or R¹² and R¹³, together with the     nitrogen to which they are attached, form a 3-7 membered     heterocyclic ring;     -   wherein said alkyl and aryl groups and heterocyclic ring are         optionally substituted with one to three R²⁰ groups; -   R¹⁴ at each occurrence is independently selected from C₁-C₆ alkyl,     C₆-C₁₀ aryl, and arylalkyl;     -   wherein said alkyl, aryl and arylalkyl groups are optionally         substituted with one to three R²⁰ groups; -   R²⁰ at each occurrence is independently selected from F, Cl, Br, I,     OR²², OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl optionally     substituted by one to three OH, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇     cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5 or 6 membered     heteroaryl, arylalkyl, C(═O)R²², CO₂R²², OC(═O)R²², C(═O)NR²³R²⁴,     NR²¹C(═O)R²², NR²¹CO₂R²², OC(═O)NR²³R²⁴, NR²¹C(═S)R²², and     S(O)_(y)R²²; -   R²¹ at each occurrence is independently selected from H and C₁-C₆     alkyl; -   R²² at each occurrence is independently selected from H, C₁-C₆     alkyl, and C₆-C₁₀ aryl; -   R²³ and R²⁴ at each occurrence are each independently selected from     H, C₁-C₆ alkyl, and C₆-C₁₀ aryl, or R²³ and R²⁴, together with the     nitrogen to which they are attached, form a 3-7 membered     heterocyclic ring; -   R²⁵ at each occurrence is independently the residue of an amino acid     after the hydroxyl group of the carboxyl group is removed; -   m is 0 or 1; -   n is 0 or 1; -   q is 0, 1, or 2; -   y is 0, 1, or 2;     and the stereoisomeric forms, mixtures of stereoisomeric forms or     pharmaceutically acceptable salts forms thereof,     for the manufacture of a medicament useful for the treatment of a     sleep-affecting disease or disorder in order to promote wakefulness.

39. A use of a compound of formula (A)

wherein:

-   Ar is independently selected from C₆-C₁₀ aryl and 5 to 10-membered     heteroaryl wherein:     -   C₆-C₁₀ aryl and heteroaryl are optionally substituted with one         to three groups selected from F, Cl, Br, I, OR²², OR²⁵, NR²³R²⁴,         NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,         C₃-C₇ cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5 or 6         membered heteroaryl, arylalkyl, C(═O)R²², CO₂R²², OC(═O)R²²,         C(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²¹CO₂R²², OC(═O)NR²³R²⁴,         NR²¹C(═S)R²², and S(O)_(y)R²²; -   X is O, S(O)_(y), N(R¹⁰), OC(R²²)₂, (R²²)₂C—O, C(R²²)₂NR²¹,     NR²¹C(R²²)₂, C(═O)N(R²¹), NR²¹C(═O), S(O)₂—NR²², NR²²S(O)₂,     C(R²²)₂C(R²²)₂, CR²¹═CR²¹, C≡C; -   Y is C₁-C₆ alkylene; or     -   (C₁-C₄ alkylene)_(m)-Z-(C₁-C₄ alkylene)_(n);     -   wherein said alkylene groups are optionally substituted with one         to three R²⁰ groups; -   Z is O, NR^(10A), S(O)_(y), CR²¹═CR²¹, C≡C, C₆-C₁₀ arylene, 5-10     membered heteroarylene, C₃-C₆ cycloalkylene, or 3-6 membered     heterocyclo-alkylene; wherein said arylene, heteroarylene,     cycloalkylene, and heterocycloalkylene groups are optionally     substituted with one to three R²⁰ groups; -   R¹ is selected from C₆-C₁₀ aryl, NR¹²R¹³, NR²¹C(═O)R¹⁴, C(═O)R¹⁴,     CO₂R¹¹, OC(═O)R¹¹, C(═O)NR¹²R¹³, C(═NR¹¹)NR¹²R¹³, OC(═O)NR¹²R¹³,     NR²¹S(O)₂R¹¹, NR²¹C(═O)NR¹²R¹³, and NR²¹S(O)₂NR¹²R¹³;     -   wherein said aryl groups are optionally substituted with one to         three R²⁰ groups; -   R² and R³ are each independently selected from F, Cl, Br, I, OR²²,     OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆     alkynyl, C₃-C₇ cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5     or 6 membered heteroaryl, arylalkyl, C(═O)R²², CO₂R²², OC(═O)R²²,     C(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²¹CO₂R²², OC(═O)NR²³R²⁴, NR²¹C(═S)R²²,     and S(O)_(y)R²²; -   R¹⁰ and R^(10A) are each independently selected from H, C₁-C₆ alkyl,     C₆-C₁₀ aryl, C(═O)R¹⁴, and S(O)_(y)R¹⁴; wherein said alkyl and aryl     groups are optionally substituted with one to three R²⁰ groups; -   R¹¹ at each occurrence is independently selected from H, C₁-C₆     alkyl, and C₆-C₁₀ aryl; wherein said alkyl and aryl groups are     optionally substituted with one to three R²⁰ groups; -   R¹² and R¹³ at each occurrence are each independently selected from     H, C₁-C₆ alkyl, and C₆-C₁₀ aryl, or R¹² and R¹³, together with the     nitrogen to which they are attached, form a 3-7 membered     heterocyclic ring;     -   wherein said alkyl and aryl groups and heterocyclic ring are         optionally substituted with one to three R²⁰ groups; -   R¹⁴ at each occurrence is independently selected from C₁-C₆ alkyl,     C₆-C₁₀ aryl, and arylalkyl;     -   wherein said alkyl, aryl and arylalkyl groups are optionally         substituted with one to three R²⁰ groups; -   R²⁰ at each occurrence is independently selected from F, Cl, Br, I,     OR²², OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl optionally     substituted by one to three OH, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇     cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5 or 6 membered     heteroaryl, arylalkyl, C(═O)R²², CO₂R²², OC(═O)R²², C(═O)NR²³R²⁴,     NR²¹C(═O)R²², NR²¹CO₂R²², OC(═O)NR²³R²⁴, NR²¹C(═S)R²², and     S(O)_(y)R²²; -   R²¹ at each occurrence is independently selected from H and C₁-C₆     alkyl; -   R²² at each occurrence is independently selected from H, C₁-C₆     alkyl, and C₆-C₁₀ aryl; -   R²³ and R²⁴ at each occurrence are each independently selected from     H, C₁-C₆ alkyl, and C₆-C₁₀ aryl, or R²³ and R²⁴, together with the     nitrogen to which they are attached, form a 3-7 membered     heterocyclic ring; -   R²⁵ at each occurrence is independently the residue of an amino acid     after the hydroxyl group of the carboxyl group is removed; -   m is 0 or 1; -   n is 0 or 1; -   q is 0, 1, or 2; -   y is 0, 1, or 2;     and the stereoisomeric forms, mixtures of stereoisomeric forms or     pharmaceutically acceptable salts forms thereof,     for the manufacture of a medicament useful for treating a     neurological disease or disorder selected from Parkinson's disease;     Alzheimer disease; attention deficit disorder; attention deficit     hyperactivity disorder; depression; and fatigue associated with a     neurological disease or disorder.

40. A pharmaceutical composition comprising a compound of formula (A)

wherein:

-   Ar is independently selected from C₆-C₁₀ aryl and 5 to 10-membered     heteroaryl wherein:     -   C₆-C₁₀ aryl and heteroaryl are optionally substituted with one         to three groups selected from F, Cl, Br, I, OR²², OR²⁵, NR²³R²⁴,         NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,         C₃-C₇ cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5 or 6         membered heteroaryl, arylalkyl, C(═O)R²², CO₂R²², OC(═O)R²²,         C(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²¹CO₂R²², OC(═O)NR²³R²⁴,         NR²¹C(═S)R²², and S(O)_(y)R²²; -   X is O, S(O)_(y), N(R¹⁰), OC(R²²)₂, (R²²)₂C—O, C(R²²)₂NR²¹,     NR²¹C(R²²)₂, C(═O)N(R²¹), NR²¹C(═O), S(O)₂NR²², NR²²S(O)₂,     C(R²²)₂C(R²²)₂, CR²¹═CR²¹, C≡C; -   Y is C₁-C₆ alkylene; or     -   (C₁-C₄ alkylene)_(m)-Z-(C₁-C₄ alkylene)_(n);     -   wherein said alkylene groups are optionally substituted with one         to three R²⁰ groups; -   Z is O, NR^(10A), S(O)_(y), CR²¹═CR²¹, C≡C, C₆-C₁₀arylene, 5-10     membered heteroarylene, C₃-C₆ cycloalkylene, or 3-6 membered     heterocyclo-alkylene; wherein said arylene, heteroarylene,     cycloalkylene, and heterocycloalkylene groups are optionally     substituted with one to three R²⁰ groups; -   R¹ is selected from NR¹²R¹³, NR²¹C(═O)R¹⁴, C(═O)R¹⁴, CO₂R¹¹,     OC(═O)R¹¹, C(═O)NR¹²R¹³, C(═NR¹¹)NR¹²R¹³, OC(═O)NR¹²R¹³,     NR²¹S(O)₂R¹¹, NR²¹C(═O)NR¹²R¹³, and NR²¹S(O)₂NR¹²R¹³;     -   wherein said aryl groups are optionally substituted with one to         three R²⁰ groups; -   R² and R³ are each independently selected from F, Cl, Br, I, OR²²,     OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆     alkynyl, C₃-C₇ cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5     or 6 membered heteroaryl, arylalkyl, C(═O)R²², CO₂R²², OC(═O)R²²,     C(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²¹CO₂R²², OC(═O)NR²³R²⁴, NR²¹C(═S)R²²,     and S(O)_(y)R²²; -   R¹⁰ and R^(10A) are each independently selected from H, C₁-C₆ alkyl,     C₆-C₁₀ aryl, C(═O)R¹⁴, and S(O)_(y)R¹⁴; wherein said alkyl and aryl     groups are optionally substituted with one to three R²⁰ groups; -   R¹¹ at each occurrence is independently selected from H, C₁-C₆     alkyl, and C₆-C₁₀ aryl;     -   wherein said alkyl and aryl groups are optionally substituted         with one to three R²⁰ groups; -   R¹² and R¹³ at each occurrence are each independently selected from     H, C₁-C₆ alkyl, or R¹² and R¹³, together with the nitrogen to which     they are attached, form a 3-7 membered heterocyclic ring;     -   wherein said alkyl group and heterocyclic ring are optionally         substituted with one to three R²⁰ groups; -   R¹⁴ at each occurrence is independently selected from C₁-C₆ alkyl,     C₆-C₁₀ aryl, and arylalkyl;     -   wherein said alkyl, aryl and arylalkyl groups are optionally         substituted with one to three R²⁰ groups; -   R²⁰ at each occurrence is independently selected from F, Cl, Br, I,     OR²², OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl optionally     substituted by one to three OH, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇     cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5 or 6 membered     heteroaryl, arylalkyl, C(═O)R²², CO₂R²², OC(═O)R²², C(═O)NR²³R²⁴,     NR²¹C(═O)R²², NR²¹CO₂R²², OC(═O)NR²³R²⁴, NR²¹C(═S)R²², and     S(O)_(y)R²²; -   R²¹ at each occurrence is independently selected from H and C₁-C₆     alkyl; -   R²² at each occurrence is independently selected from H, C₁-C₆     alkyl, and C₆-C₁₀ aryl; -   R²³ and R²⁴ at each occurrence are each independently selected from     H, C₁-C₆ alkyl, and C₆-C₁₀ aryl, or R²³ and R²⁴, together with the     nitrogen to which they are attached, form a 3-7 membered     heterocyclic ring; -   R²⁵ at each occurrence is independently the residue of an amino acid     after the hydroxyl group of the carboxyl group is removed; -   m is 0 or 1; -   n is 0 or 1; -   q is 0, 1, or 2; -   y is 0, 1, or 2;     and the stereoisomeric forms, mixtures of stereoisomeric forms or     pharmaceutically acceptable salts forms thereof,     in admixture with one or more pharmaceutically acceptable     excipients.

41. A method for preparing a compound of claims 1 to 35, comprising the steps of:

-   -   i) reacting a thiouronium compound (E) with a reactant of         structure LG-YR¹ to form a compound of formula (I):

-   -   wherein Ar, X, R², R³, Y, R¹ are as defined in claim 1, q=0 and         LG represents a leaving group; and optionally     -   ii) isolating the formed compound of formula (I).

42. The method of claim 41, wherein step i) comprises

-   -   a) converting the compound of formula (E) into the corresponding         thiol compound and     -   b) reacting the obtained thiol compound with the reactant         LG-Y—R¹.

43. The method of claims 41 or 42, wherein the compound (E) is formed by reacting the compound (D) with thiourea and a suitable acid HA:

-   -   wherein Ar, X, R², R³ are as defined in claim 1.

44. The method of claim 43, wherein the compound (D) is formed by reacting a compound (C) with a suitable reducing agent:

-   -   wherein Ar, X, R², R³ are as defined in claim 1 and W is C(═O)H         or COOH.

45. The method according to claim 44, wherein compound (C) is formed by reacting a compound (A) with a compound (B):

46. The method according to any of claims 41 to 45, wherein the compound formed at step i) is a compound of formula (I) wherein q is 0, R¹ is COOR, and R represents H or (C₁-C₆) alkyl:

47. The method according to claim 46 further comprising:

-   -   a1) reacting the carboxylic acid or ester of formula (I) with an         appropriate amine of general structure NHR¹²R¹³, wherein R¹² and         R¹³ are as defined in claim 1; and optionally     -   b1) isolating the obtained compound of formula (I) wherein R¹ is         C(═O)NR¹²R¹³.

48. The method of any of claims 46 or 47 further comprising:

-   -   a2) oxidizing the compound of formula (I) wherein q is 0; and         optionally     -   b2) isolating the obtained compound of formula (I) wherein q is         1 or 2.

Although the present invention has been described in considerable detail, those skilled in the art will appreciate that numerous changes and modifications may be made to the embodiments and preferred embodiments of the invention and that such changes and modifications may be made without departing from the spirit of the invention. It is therefore intended that the appended claims cover all equivalent variations as fall within the scope of the invention. 

1. A compound of formula (A):

wherein : Ar is C₆-C₁₀ aryl wherein: C₆-C₁₀ aryl is optionally substituted with one to three groups selected from F, Cl, Br, I, OR²², OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5 or 6 membered heteroaryl, arylalkyl, C(═O)R²², CO₂R²², OC(═O)R²², C(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²¹CO₂R²², OC(═O)NR²³R²⁴, NR²¹C(═S)R²², and S(O)_(y)R²²; X is O, S(O)_(y), N(R¹⁰), OC(R²²)₂, (R²²)₂CO, C(R²²)₂NR²¹, NR²¹C(R²²)₂, C(═O)N(R²¹), NR²¹C(═O), S(O)₂—NR²², NR²²S(O)₂, C(R²²)₂C(R²²)₂, CR²¹═CR²¹, or C≡C; Y is C₁-C₆ alkylene; or (C₁-C₄ alkylene)_(m)-Z—(C₁-C₄ alkylene)_(n); wherein said alkylene groups are optionally substituted with one to three R²⁰ groups; Z is O, NR^(10A), S(O)_(y), CR²¹═CR²¹, C≡C, C₆-C₁₀ arylene, 5-10 membered heteroarylene, 3-6 membered heterocycloalkylene, or C₃-C₆ cycloalkylene, wherein said arylene, heteroarylene, heterocycloalkylene, and cycloalkylene groups are optionally substituted with one to three R²⁰ groups; R¹ is selected from NR¹²R¹³, C(═O)NR¹²R¹³, C(═NR¹¹)NR¹²R¹³, OC(═O)NR¹²R¹³, NR²¹C(═O)NR¹²R¹³, and NR²¹S(O)₂NR¹²R¹³; R² and R³ are each independently selected from H, F, Cl, Br, I, OR²², OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5 or 6 membered heteroaryl, arylalkyl, C(═O)R²², CO₂R²², OC(═O)R²², C(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²¹CO₂R²², OC(═O)NR²³R²⁴, NR²¹C(═S)R²², and S(O)_(y)R²²; R¹⁰ and R^(10A) are each independently selected from H, C₁-C₆ alkyl, C₆-C₁₀ aryl, C(═O)R¹⁴, and S(O)_(y)R¹⁴; wherein said alkyl and aryl groups are optionally substituted with one to three R²⁰ groups; R¹¹ at each occurrence is independently selected from H, C₃-C₇ alkyl and C₆-C₁₀ aryl; wherein said alkyl and aryl group are optionally substituted with one to three R²⁰ groups; R¹² and R¹³ together with the nitrogen to which they are attached, form a 3-7 membered heterocyclic ring; wherein said heterocyclic ring is optionally substituted with one to three R²⁰ groups; R¹⁴ at each occurrence is independently selected from C₁-C₆ alkyl, C₆-C₁₀ aryl, and arylalkyl; wherein said alkyl, aryl and arylalkyl groups are optionally substituted with one to three R²⁰ groups; R²⁰ at each occurrence is independently selected from F, Cl, Br, I, OR²², OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl optionally substituted by one to three OH, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5 or 6 membered heteroaryl, arylalkyl, C(═O)R²², CO₂R²², OC(═O)R²², C(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²¹CO₂R²², OC(═O)NR²³R²⁴, NR²¹C(═S)R²², and S(O)_(y)R²²; R²¹ at each occurrence is independently selected from H and C₁-C₆ alkyl; R²² at each occurrence is independently selected from H, C₁-C₆ alkyl, and C₆-C₁₀ aryl; R²³ and R²⁴ at each occurrence are each independently selected from H, C₁-C₆ alkyl, and C₆-C₁₀ aryl, or R²³ and R²⁴, together with the nitrogen to which they are attached, form a 3-7 membered heterocyclic ring; R²⁵ at each occurrence is independently the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; m is 0 or 1; n is 0 or 1; q is 1 or 2; y is 0, 1, or 2; Ar—X is positioned ortho or para to —CH₂—S(O)_(q)—Y—R¹; with the exclusion of the compounds wherein: Y is C₂ alkylene substituted with one to three C₁-C₆ alkylene and/or NR²³R²⁴ and/or NR²¹CO₂R²², and R¹ is C(═O)NR¹²R¹³; or a stereoisomeric form, mixture of stereoisomeric forms or a pharmaceutically acceptable salt form thereof.
 2. A compound as defined in claim 1, wherein Y is C₁-C₆ alkylene, (C₁-C₄ alkylene)_(m)-Z¹—(C₁-C₄ alkylene)_(n), or C₁-C₄ alkylene-Z²—C₁-C₄ alkylene, wherein: said alkylene groups are optionally substituted with one to three R²⁰ groups; Z¹ is CR²¹═CR²¹, C≡C, C₆-C₁₀ arylene, 5-10 membered heteroarylene, 3-6 membered heterocycloalkylene, or C₃-C₆ cycloalkylene; wherein said arylene, heteroarylene, heterocycloalkylene, and cycloalkylene groups are optionally substituted with one to three R²⁰ groups; and Z² is O, NR^(10A), or S(O)_(y).
 3. A compound as defined in claim 1, wherein q is
 1. 4. A compound as defined in claim 1, wherein R¹ is selected from NR¹²R¹³; C(═O)NR¹²R¹³; C(═NR¹¹)NR¹²R¹³; and NR²¹C(═O)NR¹²R¹³.
 5. A compound as defined in claim 4, wherein R¹ is C(═O)NR¹²R¹³.
 6. A compound as defined in claim 3, wherein R¹ is selected from C(═O)NR¹²R¹³, OC(═O)NR¹²R¹³, and NR²¹S(O)₂NR¹²R¹³.
 7. A compound as defined in claim 1, wherein X is O, S(O)_(y),N(R¹⁰).
 8. A compound as defined in claim 1, wherein X is OC(R²²)₂, C(R²²)₂O, C(R²²)₂NR²¹, NR²¹C(R²²)₂, C(═O)N(R²¹), NR²¹C(═O), S(O)₂NR²², NR²²S(O)₂, C(R²²)₂C(R²²)₂.
 9. A compound as defined in claim 8, wherein X is OC(R²²)₂, C(R²²)₂NR²¹, C(═O)N(R²¹), S(O)₂—NR²².
 10. A compound as defined in claim 1, wherein Y is C₁-C₆ alkylene.
 11. A compound as defined in claim 10, wherein Y is CH₂.
 12. A compound as defined in claim 2, wherein Y is (C₁-C₄ alkylene)_(m)-Z¹—(C₁-C₄ alkylene)_(n).
 13. A compound as defined in claim 12, wherein Z¹ is C₆-C₁₀ arylene or C₃-C₆ cycloalkylene.
 14. A compound as defined in claim 13, wherein Z¹ is phenylene.
 15. A compound as defined in claim 12, wherein Z¹ is 5-10 membered heteroarylene or 3-6 membered heterocyloalkylene.
 16. A compound as defined in claim 12, wherein Z¹ is CR²¹═CR²¹ or C≡C.
 17. A compound as defined in claim 2, wherein Y is C₁-C₄ alkylene-Z²—C₁-C₄ alkylene.
 18. A compound as defined in claim 17, wherein Z² is O.
 19. A compound as defined in claim 1, with the structure:

wherein: Ar is optionally substituted with one to three groups selected from F, Cl, Br, I, OR²², OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, C₁-C₆ alkyl, phenyl, arylalkyl, and C(═O)R²²; X is O, S(O)_(y), N(R¹⁰), OC(R²²)₂, C(R²²)₂O, C(R²²)₂NR²¹, NR²¹C(R²²)₂, C(═O)N(R²¹), NR²¹C(═), S(═O)₂NR²², NR²²S(═O)₂; Y is C₁-C₆ alkylene; C₁-C₄ alkylene-Z¹—(C₁-C₄ alkylene)_(n); or C₁-C₄ alkylene-Z²—C₁-C₄ alkylene; wherein said alkylene groups are optionally substituted with one to three R²⁰ groups; Z¹ is CR²¹═CR²¹, C≡C, C₆-C₁₀ arylene, 5-10 membered heteroarylene, 3-6 membered heterocycloalkylene, or C₃-C₆ cycloalkylene; Z² is O, NR^(10A), or S(O)_(y); R¹ is selected from C(═O)NR¹²R¹³, C(═NR¹¹)NR¹²R¹³, OC(═O)NR¹²R¹³, NR²¹C(═O)NR¹²R¹³, and NR²¹S(O)₂NR¹²R¹³; R² and R³ are each independently selected from H, F, Cl, Br, I, OR²², OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl, phenyl, 5 or 6 membered heteroaryl, arylalkyl, C(═O)R²²; R¹⁰ and R^(10A) are each independently selected from H, C₁-C₆ alkyl, C(═O)R¹⁴, and S(O)_(y)R¹⁴; wherein said alkyl groups are optionally substituted with one to three R²⁰ groups; R¹¹ at each occurrence is independently selected from H or C₃-C₇ alkyl, wherein said alkyl group is optionally substituted with one to three R²⁰ groups; R¹² and R¹³ together with the nitrogen to which they are attached, form a 3-7 membered heterocyclic ring; wherein said heterocyclic ring is optionally substituted with one to three R²⁰ groups; R¹⁴ at each occurrence is independently selected from C₁-C₆ alkyl, C₆-C₁₀ aryl, and arylalkyl; wherein said alkyl, aryl and arylalkyl groups are optionally substituted with one to three R²⁰ groups; R²⁰ at each occurrence is independently selected from F, Cl, Br, I, OR²², OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, phenyl, benzyl, C(═O)R²², CO₂R²², OC(═O)R²², C(═O)NR²³R²⁴, NR²¹C(═O)R²², NR²¹CO₂R²², OC(═O)NR²³R²⁴, NR²¹C(═S)R²², and S(O)_(y)R²²; R²¹ at each occurrence is independently selected from H and C₁-C₆ alkyl; R²² at each occurrence is independently selected from H, C₁-C₆ alkyl, and C₆-C₁₀ aryl; R²³ and R²⁴ at each occurrence are each independently selected from H, and C₁-C₆ alkyl, or R²³ and R²⁴, together with the nitrogen to which they are attached, form a 3-7 membered heterocyclic ring; R²⁵ at each occurrence is independently the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; n is 0 or 1; y is 0, 1, or 2; or a stereoisomeric form, mixture of stereoisomeric forms or a pharmaceutically acceptable salt form thereof.
 20. A compound as defined in claim 19, wherein: Y is C₁-C₆ alkylene, C₁-C₄ alkylene-Z¹—C₁-C₄ alkylene, or C₁-C₄ alkylene-Z²—C₁-C₄ alkylene, wherein said alkylene groups are optionally substituted with one to three C₁-C₆ alkyl groups; Z¹ is CR²¹═CR²¹, C≡C, or phenyl; Z² is O, NR^(10A), or S(O)_(y); X is O, S(O)_(y), N(R¹⁰), OC(R²²)₂, C(R²²)₂O, C(R²²)₂NR²¹, NR²¹C(R²²)₂, C(═O)N(R²¹), NR²¹C(═O), S(O)₂NR²², NR²²S(O)₂; and R¹ is C(═O)NR¹²R¹³.
 21. A compound as defined in claim 19, having the structure of formula (Ib):

or a stereoisomeric form, mixture of stereoisomeric forms or a pharmaceutically acceptable salt form thereof.
 22. A compound as defined in claim 21, wherein X is O, S(O)_(y), N(R¹⁰), OC(R²²)₂, C(R²²)₂O, C(R²²)₂NR²¹, NR²¹C(R²²)₂, C(═O)N(R²¹), NR²¹C(═O), S(O)₂—NR²², or NR²²S(O)₂.
 23. A compound as defined in claim 22, wherein X is O, S(O)_(y), or NH.
 24. A compound as defined in claim 22, wherein X is OCH₂, CH₂O, CH₂NH, NHCH₂, C(═O)NH, NHC(═O), S(O)₂NH, or NHS(O)₂.
 25. A compound as defined in claim 22, wherein X is NH, O—CH₂, CH₂NH, C(═O)NH, or S(O)₂—NH.
 26. A compound as defined in any of claim 1, 19, or 21, wherein R² and R³ are each independently selected from H, F, Cl, Br, I, OR²², OR²⁵, NR²³R²⁴, NHOH, NO₂, CN, CF₃, C₁-C₆ alkyl, phenyl, 5 or 6 membered heteroaryl, arylalkyl, and C(═O)R²².
 27. A compound as defined in claim 21, wherein Y is C₁-C₆ alkylene.
 28. A compound as defined in claim 27, wherein Y is CH₂.
 29. A compound as defined in claim 21, wherein Y is (C₁-C₄ alkylene)_(n)-Z¹—C₁-C₄ alkylene and Z¹ is phenyl, 5 or 6 membered heteroarylene, CR²¹═CR²¹, or C≡C.
 30. A compound selected in accordance with the following table, wherein : TABLE 1

Ex. Posi- No. Ar X tion* R² R³ q Y—R¹ 13 3,4-DiClPh O para H H 0 CH₂CO—N- piperazinyl-N-Boc 14 3,4-DiClPh O para H H 0 CH₂CO—N- piperazinyl 19 3,4-DiClPh O para H H 1 CH₂CO—N- piperazinyl 16 4-ClPh S para H H 0 CH₂CO-1-(4-acetyl)- piperazinyl 23 4-ClPh S para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 24 4-ClPh SO para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl Ph O meta H H 0 CH₂CO—N- pyrrolidinyl 31 Ph O meta H H 1 CH₂CO—N- pyrrolidinyl Ph O meta H H 0 CH₂CO-1-(4-acetyl)- piperazinyl 35 Ph O meta H H 1 CH₂CO-1-(4- acetyl)-piperazinyl 4-OCH₃Ph O para H H 0 CH₂CO-1-(4-acetyl)- piperazinyl 37 4-OCH₃Ph O para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 4-OCH₃Ph O para H H 0 CH₂CO—N- piperazinyl 38 4-OCH₃Ph O para H H 1 CH₂CO—N- piperazinyl 11 3,4-DiClPh O para H H 0 CH₂CO-1-(4-acetyl)- piperazinyl 22 3,4-DiClPh O para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 27 3,4-DiClPh O para H H 2 CH₂CO-1-(4-acetyl)- piperazinyl 3,4-DiClPh O ortho H H 0 CH₂CO-1-(4-acetyl)- piperazinyl 40 3,4-DiClPh O ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 3,4-DiClPh O para H H 0 CH₂CO-1-(4- carboxamide)- piperazinyl 41 3,4-DiClPh O para H H 1 CH₂CO-1-(4- carboxamide)- piperazinyl 2-ClPh O para H H 0 CH₂CO-1-(4-acetyl)- piperazinyl 46 2-ClPh O para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 2-ClPh O para H H 0 CH₂CO—N- piperazinyl 47 2-ClPh O para H H 1 CH₂CO—N- piperazinyl 4-FPh O para H H 0 CH₂CO-1-(4-acetyl)- piperazinyl 48 4-FPh O para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 95 4-FPh O para H H 2 CH₂CO-1-(4-acetyl)- piperazinyl 4-FPh O ortho H H 0 CH₂CO-1-(4-acetyl)- piperazinyl 49 4-FPh O ortho H H 1 CH₂CO-1-(4- acetyl)-piperazinyl 2-Naphthyl O ortho H H 0 CH₂CO-1-(4-acetyl)- piperazinyl 53 2-Naphthyl O ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 2-ClPh O ortho H H 0 CH₂CO-1-(4-acetyl)- piperazinyl 57 2-ClPh O ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 2-Naphthyl O para H H 0 CH₂CO-1-(4-acetyl)- piperazinyl 58 2-Naphthyl O para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 2-BiPh O ortho H H 0 CH₂CO-1-(4-acetyl)- piperazinyl 59 2-BiPh O ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 2-BiPh O para H H 0 CH₂CO-1-(4-acetyl)- piperazinyl 60 2-BiPh O para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 4-ClPh O para H H 0 CH₂CO-1-(4-acetyl)- piperazinyl 61 4-ClPh O para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 4-OCH₃Ph O para H H 0 CH₂CO-1-(4-methyl)- piperazinyl 62 4-OCH₃Ph O para H H 1 CH₂CO-1-(4-methyl)- piperazinyl 3,4-DiClPh O para H H 0 CH₂CO-1-(4- ethylcarboxylate)- piperazinyl 63 3,4-DiClPh O para H H 1 CH₂CO-1-(4- ethylcarboxylate)- piperazinyl 4-FPh O para H H 0 CH₂CO-1-(4- hydroxyethyl)- piperazinyl 64 4-FPh O para H H 1 CH₂CO-1-(4- hydroxyethyl)- piperazinyl 3,4-DiClPh O ortho H H 0 CH₂CO-1-(4- hydroxyethyl)- piperazinyl 65 3,4-DiClPh O ortho H H 1 CH₂CO-1-(4- hydroxyethyl)- piperazinyl 4-FPh O para H H 0 CH₂CO-1-(4-methyl)- piperazinyl 66 4-FPh O para H H 1 CH₂CO-1-(4-methyl)- piperazinyl 4-FPh O para H H 0 CH₂CO-1-(4- ethylcarboxylate)- piperazinyl 68 4-FPh O para H H 1 CH₂CO-1-(4- ethylcarboxylate)- piperazinyl 4-OCH₃Ph O para H H 0 CH₂CO-1-(4- ethylcarboxylate)- piperazinyl 69 4-OCH₃Ph O para H H 1 CH₂CO-1-(4- ethylcarboxylate)- piperazinyl 4-ClPh S para H H 0 CH₂CO-1-(4- ethylcarboxylate)- piperazinyl 70 4-ClPh S para H H 1 CH₂CO-1-(4- ethylcarboxylate)- piperazinyl 71 4-ClPh SO para H H 1 CH₂CO-1-(4- ethylcarboxylate)- piperazinyl 3,4-DiClPh O ortho H H 0 CH₂CO-1-(4- ethylcarboxylate)- piperazinyl 72 3,4-DiClPh O ortho H H 1 CH₂CO-1-(4- ethylcarboxylate)- piperazinyl Ph O ortho H H 0 CH₂CO—N- pyrrolidinyl 98 Ph O ortho H H 1 CH₂CO—N- pyrrolidinyl Ph O para H H 0 CH₂CO—N- pyrrolidinyl 101 Ph O para H H 1 CH₂CO—N- pyrrolidinyl Ph O ortho H H 0 CH₂CO-1-(4- hydroxy)-piperidinyl 106 Ph O ortho H H 1 CH₂CO-1-(4- hydroxy)-piperidinyl Ph O ortho H H 0 CH₂CO-1-(4-acetyl)- piperazinyl 107 Ph O ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl Ph O meta H H 0 CH₂CO-1-(4- hydroxy)-piperidinyl 109 Ph O meta H H 1 CH₂CO-1-(4- hydroxy)-piperidinyl 110 Ph O para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 112 Ph O para H H 1 CH₂CO-1-(4- hydroxy)-piperidinyl 116 4-ClPh CONH ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 121 2,4-DiOCH₃Ph CONH ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 122 3,4-DiOCH₃Ph CONH ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 123 4-FPh CONH ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 124 3,4-DiClPh CONH ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 4-ClPh S ortho H H 0 CH₂CO—N- piperazinyl 73 4-ClPh S ortho H H 1 CH₂CO—N- piperazinyl 2,3-DiClPh O ortho H H 0 CH₂CO-1-(4-acetyl)- piperazinyl 74 2,3-DiClPh O ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 2,5-DiClPh O ortho H H 0 CH₂CO-1-(4-acetyl)- piperazinyl 75 2,5-DiClPh O ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 2,4-DiClPh O para H H 0 CH₂CO-1-(4-acetyl)- piperazinyl 78 2,4-DiClPh O para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 2,4-DiClPh O ortho H H 0 CH₂CO-1-(4-acetyl)- piperazinyl 79 2,4-DiClPh O ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 3,5-DiClPh O ortho H H 0 CH₂CO-1-(4-acetyl)- piperazinyl 82 3,5-DiClPh O ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 3,5-DiClPh O para H H 0 CH₂CO-1-(4-acetyl)- piperazinyl 83 3,5-DiClPh O para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 2,5-DiClPh O para H H 0 CH₂CO-1-(4-acetyl)- piperazinyl 86 2,5-DiClPh O para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 3,4-DiClPh S para H H 0 CH₂CO-1-(4-acetyl)- piperazinyl 87 3,4-DiClPh S para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 2,3-DiClPh O para H H 0 CH₂CO-1-(4-acetyl)- piperazinyl 90 2,3-DiClPh O para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 2,6-DiClPh O para H H 0 CH₂CO-1-(4-acetyl)- piperazinyl 91 2,6-DiClPh O para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 135 Ph NH ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 136 Ph NH para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 134 4-OCH₃Ph NH ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 131 4-FPh SO₂NH para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 137 4-OCH₃Ph NH para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 138 4-FPh NH para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 139 4-ClPh NH para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 140 4-FPh NH para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 128 3,4-DiClPh CONH para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 129 4-FPh CONH para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 141 3,4-DiClPh NH para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 132 4-ClPh SO₂NH para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 147 4-FPh CH₂NH para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 133 3,4-DiClPh SO₂NH para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 148 3,4-DiClPh CH₂NH para H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 149 4-FPh CH₂NH ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 146 3,4-DiClPh CH₂NH ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 130 3,4-DiClPh SO₂NH ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 145 2-Furyl CH₂NH ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 144 2-Thienyl CH₂NH ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 142 2-Thienyl CONH ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 143 2-Furyl CONH ortho H H 1 CH₂CO-1-(4-acetyl)- piperazinyl 17 4-ClPh O para 2′- H 0 CH₂CO-1-(4-acetyl)- Cl piperazinyl 25 4-ClPh O para 2′- H 1 CH₂CO-1-(4-acetyl)- Cl piperazinyl Ph = phenyl, ClPh = chlorophenyl, DiClPh = di-chlorophenyl, FPh = fluorophenyl; *Position: the position refers to the position of the ArX lateral side chain as compared to —CH₂—S(O)_(q)—Y—R¹ group on the central benzyl ring; ortho is position 2′, meta is position 3′ and para is position 4′; or a stereoisomeric form, mixture of stereoisomeric forms or a pharmaceutically acceptable salt form thereof.


31. A pharmaceutical composition, comprising a compound of claim 1 or a stereoisomeric form, mixture of stereoisomeric forms, or a pharmaceutically acceptable salt form thereof, in admixture with one or more pharmaceutically acceptable excipients. 